Current Biology 19, R132–R142, February 10, 2009 ª2009 Elsevier Ltd All rights reserved
DOI 10.1016/j.cub.2008.12.005
The Hair Follicle as a Dynamic Miniorgan
Marlon R. Schneider,1,#,* Ruth Schmidt-Ullrich,2,#
and Ralf Paus3,4
Hair is a primary characteristic of mammals, and exerts a
wide range of functions including thermoregulation, physical protection, sensory activity, and social interactions.
The hair shaft consists of terminally differentiated keratinocytes that are produced by the hair follicle. Hair follicle
development takes place during fetal skin development
and relies on tightly regulated ectodermal–mesodermal
interactions. After birth, mature and actively growing
hair follicles eventually become anchored in the subcutis,
and periodically regenerate by spontaneously undergoing
repetitive cycles of growth (anagen), apoptosis-driven
regression (catagen), and relative quiescence (telogen).
Our molecular understanding of hair follicle biology relies
heavily on mouse mutants with abnormalities in hair structure, growth, and/or pigmentation. These mice have
allowed novel insights into important general molecular
and cellular processes beyond skin and hair biology,
ranging from organ induction, morphogenesis and regeneration, to pigment and stem cell biology, cell proliferation,
migration and apoptosis. In this review, we present basic
concepts of hair follicle biology and summarize important
recent advances in the field.
Introduction
Hair is composed of terminally differentiated, dead keratinocytes (trichocytes), which are compacted into a fibre of
amazing tensile strength, the hair shaft. The presence of
hair is characteristic for mammals, in which it exerts a wide
range of tasks. These include physical protection, thermal
insulation, camouflage, dispersion of sweat and sebum,
sensory and tactile functions, and social interactions. In
human society, hair is of enormous, psychosocial importance, and many human diseases are associated with hair
loss or, less frequently, with overabundance of hair (Box 1).
As inappropriate hair growth can cause considerable
suffering in the affected individual, there is an ever-increasing
demand for drugs that manipulate hair abundance and
appearance [1–3].
Hair shafts are made by the hair follicle, a complex miniorgan of the skin, which constitutes the pilosebaceous unit
together with its associated structures, the sebaceous
gland, the apocrine gland and the arrector pili muscle
(Figure 1 and Box 2). Hair follicle formation largely takes
place during fetal and perinatal skin development. However,
after skin wounding de novo hair follicle formation may also
occur in adult mouse and rabbit skin [4], and can even be
induced in adult human skin [5,6]. Hair follicle development
1Institute
of Molecular Animal Breeding and Biotechnology, Gene
Center, LMU Munich, Munich, Germany. 2Max-Delbrück-Center for
Molecular Medicine, Dept. of Signal Transduction, Berlin-Buch,
Germany. 3Dept. of Dermatology, University Hospital SchleswigHolstein, University of Lübeck, Lübeck, Germany. 4School of
Translational Medicine, University of Manchester, Manchester, UK.
#These authors contributed equally.
*E-mail: schnder@lmb.uni-muenchen.de
Review
involves tightly coordinated prototypic ectodermal–mesodermal interactions [7,8]. Ectodermal hair follicle stem cells
give rise to all epithelial components of the hair follicle,
including the sebaceous gland and apocrine gland, while
the mesoderm-derived cells will develop into the follicular
dermal papilla and the connective tissue sheath. Instead,
neural crest-derived melanocyte progenitors give rise to
the hair follicle pigmentary unit [9,10].
The hair follicle undergoes cycles of growth (anagen),
apoptosis-mediated regression (catagen) and relative quiescence (telogen) [2,11]. In each cycle, a new hair shaft is
formed, and the old hair is eventually shed, mostly in an
actively regulated process termed exogen. Generation of
the new hair shaft depends on the activation of hair-specific
epithelial stem cells, harboured in the bulge region of the hair
follicle epithelium (Figure 1B, Box 2). Although the hair follicle
is highly sensitive to numerous growth factors, cytokines,
neuropeptides and hormones, which in part are produced
by the hair follicle itself, hair follicle cycling as such is an
autonomous phenomenon that is able to continue even in
isolated hair follicles in organ culture [2,11].
Spontaneous mouse mutants as well as genetically engineered mouse models have been extremely helpful in
the molecular characterization of hair-follicle biology and
pathology [12]. Furthermore, several genes responsible for
defined hair defects have been identified in the spontaneous
mutants, which include Ragged/Opossum (abnormal hair
numbers), Waved 2 (abnormal morphogenesis), Nude and
Balding (abnormal hair shaft structure) or Lethal spotting
(abnormal hair pigmentation) (Table 1). In this review, we
will emphasize recent insights into the molecular controls
of murine hair follicle development and cycling, stem cell
biology, and pigmentation.
Functional Hair Anatomy
The mature (anagen) hair follicle can be divided into a ‘permanent’ upper part, which does not cycle visibly, and a lower
part, which is continuously remodelled in each hair cycle.
The upper part of the hair follicle consists of the infundibulum, which is the opening of the hair canal to the skin
surface, and the isthmus. The lower, cycling part represents
the actual hair shaft factory, the anagen bulb (Figure 1A) [3].
The lower end of the infundibulum is marked by the insertion
of the sebaceous gland duct — a constant trouble area in
patients with acne.
At the proximal end, the infundibulum joins the isthmus
region of the outer root sheath, where the arrector pili muscle
is inserted (Figure 1A). The lower isthmus also harbours
epithelial and melanocytic hair follicle stem cells in the
so-called bulge region. The bulge is the end of the permanent, non-cycling region. Bulge and anagen bulb, the bulbar
end of the hair follicle, are separated by a long stretch of
suprabulbar hair-follicle epithelium (Figure 1A,C). The anagen bulb contains the matrix keratinocytes and the hair
follicle pigmentary unit. Activated matrix keratinocytes,
which have migrated out of the bulge to colonize the matrix
area, are rapidly proliferating cells and their number determines hair bulb size and hair shaft diameter. When matrix
cells stop proliferating and differentiate, they give rise to
the various cell lineages of the hair shaft and the inner root
Review
R133
Box 1.
Frequent diseases of hair growth.
Alopecia
Abnormal hair loss; androgenetic alopecia is
baldness caused by miniaturization of genetically
predisposed follicles; alopecia areata (patchy hair
loss) is thought to be caused by an autoimunne
reaction to anagen follicles; scarring or cicatricial
alopecia, caused by destruction of hair follicles
after inflammation and other causes.
Anagen
Abrupt hair shedding caused by interruption of
effluvium
hair growth, for instance in patients undergoing
chemotherapy.
Hirsutism
Excessive hair growth in androgen-dependent
areas in women.
Hypertrichosis Excessive hair growth beyond the normal pattern.
Miniaturization Conversion of large terminal hairs into small vellus
hairs.
Telogen
Poorly defined thinning of scalp hair, mostly
effluvium
associated with physical or psychological stress.
sheath, while the outer root sheath is derived from separate
progenitor cells (Figure 1C,D) [13,14].
While infundibulum, isthmus, bulge and hair bulb are all
part of the hair follicle epithelium, i.e. of ectodermal origin,
the dermal papilla is mesoderm-derived. The dermal papilla
(Figure 1C,D), which consists of a small cluster of densely
packed fibroblasts, dictates hair bulb size, hair shaft diameter and length, and anagen duration [2,11,14,15].
When looking at a cross-section of the hair follicle, its
epithelium forms a cylinder with at least eight different
concentric layers, each one expressing a distinct pattern of
keratins [3]. Starting from the periphery, these layers include
the outer root sheath, the companion layer, the inner root
sheath, and finally the hair shaft (Figure 1D). In its bulge region,
the outer root sheath contains the epithelial hair follicle stem
cells [14]. The central part of the hair follicle epithelium holds
the hair shaft (see below and Figure 1D). The entire hair follicle
epithelium is surrounded by a mesoderm-derived connective
tissue sheath (Figure 1C,D), a loose accumulation of collagen
and stromal cells resting upon a basement membrane. The
hair shaft is enwrapped by the cuticle, and further components are the cortex and the medulla (Figure 1D).
In adult humans, there are two major hair types: heavily
pigmented terminal hairs, found on the scalp, and vellus
hairs, which are most abundant e.g. in facial and truncal
skin [3]. Mice display at least 8 major hair types: pelage, or
coat hairs, vibrissae or whiskers, cilia or eyelashes, tail hairs,
ear hairs, and hairs around the feet, the genital and perianal
area and the nipples [12]. Discerning these various hair types
is very important when analysing mouse hair mutants, since
distinct hair follicle populations show substantial differences
in their molecular controls [7].
Hair Follicle Development and Its Molecular Control
The key prerequisite for hair follicle development is the
molecular communication between the epidermis and the
underlying mesenchyme (Figure 2) [7,8,16]. The fundamentals of this reciprocal interaction are evolutionarily ancient
and required for the development of all ectodermal appendages across species, including scales, feathers, hair, nails
and teeth, as well as most exocrine glands [17,18]. The
signals controlling epidermal–dermal communication include
secreted molecules of the Wnt/wingless family, the hedgehog
family, and members of the TGF-b/BMP (transforming growth
factor-b/bone morphogenetic protein), FGF (fibroblast
growth factor) and TNF (tumour necrosis factor) families
[7,8,16]. Different combinations of these signals may dictate
whether a tooth or a hair follicle will develop [7,8,16].
In mice, both Wnt and BMP are essential for the development of skin epithelium, which originates from the ectoderm
Figure 1. Histomorphology of the hair follicle.
(A) Sagittal section through a human scalp
hair follicle (anagen VI) showing the permanent (infundibulum, isthmus) and anagenassociated (suprabulbar and bulbar area)
components of the hair follicle. (B) High
magnification image of the isthmus. The
dashed square indicates the approximate
location of the bulge. (C) High magnification
image of the bulb. (D) Schematic drawing
illustrating the concentric layers of the outer
root sheath (ORS), inner root sheath (IRS)
and shaft in the bulb. The inner root sheath
is composed of four layers: Companion layer
(CL), Henle’s layer, Huxley’s layer, and the
inner root sheath cuticle. The companion
layer cells are tightly bound to Henle’s layer,
but not to the outer root sheath, thus allowing
the companion layer to function as a slippage
plane between the stationary outer root
sheath and the upwards moving inner root
sheath. Further inwards, the inner root sheath
cuticle is composed of scales that interlock
with the scales of the hair shaft cuticle,
anchoring the shaft in the follicle and enabling
both layers to jointly move during hair follicle
growth. The hair shaft is wrapped by a protective layer of overlapping scales and in mice,
but not in humans, shows in its centre regularrows of air spaces believed to play a role in
thermal insulation (BM: basal membrane; APM: arrector pili muscle; CTS: connective tissue sheath; DP: dermal papilla; M: matrix; HS: hair shaft,
IRS: inner root sheath; ORS: outer root sheath; SG: sebaceous gland). (Histology kindly provided by Katja Meyer.)
Current Biology Vol 19 No 3
R134
Box 2.
Glossary of hair follicle anatomy.
Arrector pili muscle
Bulb
Bulge
Club hair
Dermal papilla
Hair canal
Hair germ
Hair peg
Hair shaft
Infundibulum
Inner root sheath
Isthmus
Outer root sheath
Pelage hairs
Sebaceous gland
Tiny smooth muscle that connects the hair follicle with the dermis. When contracted the arrector pili causes the ‘raising’
of the hair.
Thickening of the proximal end of the hair follicle. Contains rapidly proliferating, rather undifferentiated matrix cells
(transient amplifying cells), melanocytes and outer root sheath cells.
Convex protrusion of the outer root sheath in the most distal permanent portion of the hair follicle, just below the
sebaceous gland and at the insertion site of the muscle arrector pili. Contains the hair follicle stem cells.
Fully keratinized, dead hair (telogen follicle) formed during catagen and telogen.
Mesodermal signaling center of the hair follicle consisting of closely packed specialized mesenchymal fibroblasts. Framed
by the enlarged bulb matrix in anagen.
Tubular connection between the epidermal surface and the most distal part of the inner root sheath. Contains the hair
shaft.
Also called ‘hair placode’ depending on the developmental stage. Bud-like thickening in the fetal epidermis consisting of
elongated keratinocytes, which at the distal end are in touch with numerous aggregated specialized dermal fibroblasts, the
dermal condensate.
Column of keratinocytes growing into the dermis during embryonic hair follicle development (developmental stages 3-5).
The concave proximal end starts to encase the dermal condensate, the future dermal papilla.
The hair per se, composed of trichocytes, which are terminally differentiated hair follicle keratinocytes. It is composed of
the medulla, the central part with loosely connected keratinized cells and large air spaces, and the cortex, which is the bulk
of the hair shaft, consisting of keratinized cells, keratin filaments, and melanin granules in pigmented hairs.
Most proximal part of the hair follicle relative to the epidermis, extending from the sebaceous duct to the epidermal
surface. Includes the hair canal and the distal Outer root sheath.
A multilayered, rigid tube composed of terminally differentiated hair follicle keratinocytes, surrounded by the outer root
sheath.
Middle part of the hair follicle extending from the sebaceous duct to the bulge.
The outermost layer of the hair follicle. Merges proximally with the basal layer of the interfollicular epidermis and distally
with the hair bulb.
Pelage hair covers most of the body’s surface, and at the molecular level it is the most extensively studied hair type
in mice. Divided into four types: the large primary monotrich or guard hairs, the secondary intermediate awl and auchene
hairs, and the secondary downy zigzag hairs.
Acinar gland composed of lipid-filled sebocytes, localized close to the insertion of the arrector pili muscle. Secretes sebum
to the epidermal surface via a holocrine mechanism. Sebum helps making hair and skin waterproof. Together with the hair
follicle and the arrector pili muscle it forms the pilosebaceous unit.
whereas Wnt/b-catenin signalling alone decides on dermal
fate around stage E10.5 [8,19]. Once mesenchymal cells
from diverse origins populate the dermis, they start interacting with the overlying epidermis to eventually induce the
growth of regularly interspaced hair placodes [7,19]. Specific
cues from the dermis are thought to induce the overlying
epidermal keratinocytes to assume an upright position and
to start proliferating. This becomes apparent in the form of
a small epithelial ingrowth into the dermis, called the hair
placode (Figure 2). The molecular nature of the earliest
hair follicle-inducing cue from the dermis remains unclear.
Hair follicle induction results in hair placode formation, which
is followed by hair follicle organogenesis and cytodifferentiation (or maturation), each phase being characterized by
specific molecular interactions (Figure 2 and Table 2). These
three developmental phases are subdivided into eight
morphologically distinguishable developmental stages
(Figure 2) [7,20].
Canonical Wnt/b-catenin signalling provides the master
switch for hair follicle fate, as ectopic epithelial expression
of the secreted Wnt inhibitor Dkk1 or lack of epidermal
b-catenin expression results in absence of hair follicle
Table 1. Classical mouse mutants with hair follicle defects and the characterization of their molecular defect.
Mutant
Hair follicle phenotype
Gene affected
References
Ragged/Opossum
Hypoplasia of selected pellage follicles; absence of
auchene, and very few zigzag hairs
Alopecia behind the ears and on the tail; lack of
guard and zigzag hairs
Premature protein truncation in Sox18
[98]
Mutations in the Ectodysplasin-A1 gene (Eda-A1).
Defective NF-kB signaling and disturbed formation
of skin appendages
Point mutation in the epidermal growth factor
receptor gene resulting in a ‘dead’ kinase
Mutations in the gene encoding Sgk3
[99]
Insertion in the hairless gene; mutation of the
human genes causes alopecia universalis
Deletion of fibroblast growth factor 5 (FGF5)
increases anagen duration and delays initiation of
catagen
Truncation of forkhead transcription factor Foxn1
Truncation of desmosome protein Desmoglein-3
[101]
[47]
[44]
Tabby
Waved 2
Wavy hairs, curly whiskers
Fuzzy
Sparse fur, abnormal hair morphology and
acceleration of hair follicle cycling
Initially normal hair growth. Total alopecia around
the age of 3-4 weeks
Very long hairs. No defects in hair follicle
morphology or hair structure
Hairless
Angora
Nude
Balding
Lethal spotting
General alopecia, except for whiskers
Focal alopecia due to separation of inner and outer
root sheath in anagen follicles
White spots in pelage hair. Affects pigmentation
Point mutation in endothelin-3
[100]
[62]
[102]
[103]
[104]
[105]
Review
R135
Induction
Stage 0
Organogenesis
Stage 1 (placode)
Stage 2 (germ)
Cytodifferentiation
Stage 3–5 (peg)
Stage 6–8 (bulbous peg)
See Table 2 for
molecular controls of
ORS, IRS and hair
shaft formation, polarity,
shaping, innervation
etc.
See Table 2 for molecular
controls of ORS, IRS and
hair shaft formation, polarity,
shaping, innervation etc.
Epidermis
Dermis
Interacting gradients of
activators and inhibitors
creating an inductive field
in the epidermis
(pre-germ). Specialised
dermal fibroblasts gather
underneath pre-germ.
Visible hair germ
(placode).
Promotion of placode
growth: Wnt/ β-catenin.
EdaA1/EdaR/NF-κB.
Noggin/Lef-1. CTGF?
Ectodin?
P-cadherin.
Proliferation of
epidermal hair
germ cells:
Shh/Smo/Gli2, Wnt
(10b,10a)/Lef-1,
FGFs/FGF2R-IIIb.
TGFβ2?
Follistatin?
Inhibition of placode
fate in surrounding cells
and placode growth:
Dkks (Dkk1, 2, and 4).
BMPs (2, 4 and 7)
Formation of dermal
papilla:
Shh/Smo/Gli2,
PDGF-A.
Current Biology
Figure 2. Embryonic pelage hair follicle development in mice.
Murine hair follicle development can be divided into three phases: Induction, organogenesis and cytodifferentiation. The morphological characteristics of the most important stages (0–8) of prenatal hair follicle development and their molecular controls are depicted. Primary guard hair development starts as early as stage E14. Secondary hair follicle development comes in two major waves: At E16.5 for the intermediate awl and auchene
hairs, and around P0 for the downy zigzag hairs. Induction (left column): At stage 0, prior to visible hair follicle placode formation, interaction
between the epidermis and the underlying dermis, which is the likely source of the unknown first inductive signal, involves local hair follicle activators (such as Wnt/b-catenin signaling) overriding hair follicle inhibitors, thereby creating an inductive field. In subsequent stages, the hair placode
becomes visible to the eye and downward growth is initiated. At these stages the dermal condensate and future dermal papilla form. Within the
developing placode, BMP signaling has to be down-regulated by specific BMP antagonists in order to allow for placode growth. Organogenesis
(middle column) and Cytodifferentiation (right column): In the following stages 3–8, the orientation of the follicle is defined (peg stage), and the
different hair lineages develop (bulbous peg). Colors of cells do not correspond to particular signals. ORS: outer root sheath; IRS: inner root sheath.
induction [21,22]. Conversely, forced expression of a stabilized
form of b-catenin causes strongly enhanced placode formation, because epidermal keratinocytes globally adopt a hair
follicle fate [23,24]. While forced epidermal expression of
secreted Dkk1 does not rule out that the Wnt signal may
originate in the dermis, the absence of hair follicle placode
formation in mice with epithelial lack, or forced expression of
an activated b-catenin strongly suggests that Wnt signalling
in the surface ectoderm is essential for hair follicle fate [21,24].
Once hair follicle fate has been adopted by regionally
defined groups of specialized keratinocytes, placode formation and growth are initiated. Mouse pelage hair follicle development takes place in two waves, starting with the primary
(guard) hairs at E14.5, followed by secondary intermediate
(awl, auchene) and downy (zigzag) hairs between E17 and
P0. Importantly, placode formation signals vary significantly
between the different hair types (Figure 2) [7]. Growth of
primary guard hair follicles requires Eda-A1, its receptor
Edar and their downstream effector, the transcription factor
NF-kB [7]. Stimulation of the Eda-A1/Edar/NF-kB pathway
upregulates Shh and cyclin D1 expression leading to placode
growth [7,25]. In contrast, secondary awl hair follicle development is independent of Eda-A1/EdaR/NF-kB signalling, but
requires the BMP antagonist Noggin and the transcription
factor Lef-1 [26–28]. Inductive signals for zigzag hair placodes
remain unknown, but mice with suppressed NF-kB activity fail
to develop zigzag placodes [29].
Epithelial placode cells signal to the underlying mesenchyme to form the dermal condensate which will subsequently give rise to the dermal papilla. Sonic hedgehog
(Shh) is a pivotal growth signal for dermal papilla maturation
and growth (Figure 2) [30,31]. The dermal condensate itself
sends out specific growth signals to the epidermis allowing
placode growth into the underlying mesenchyme, and
further reciprocal epithelial–mesenchymal signalling will
eventually lead to maturation and formation of the different
hair follicle lineages (Figure 2 and Table 2).
Not every epidermal keratinocyte will become a follicular
keratinocyte, which results in hairless spaces between the
regular array of hair follicles. This implies that there must
be a mechanism which promotes or blocks hair follicle
fate. Local gradients of hair follicle activators and inhibitors
are believed to account for this mechanism. Eventually hair
follicle activating signals will create a morphogenetic field
by locally overriding hair follicle inhibitors [7,32–34]. While
Wnt, Eda-A1 and Noggin are bona fide hair placode-inducing
signals, the hair follicle inhibiting signals and their mechanisms of action remain to be clarified. Results from studies
with embryonic mouse skin explants show that BMP is
able to inhibit placode growth [28,35]. This is further
confirmed by the hair follicle type-specific expression of
BMP antagonists within hair follicle placodes: In guard hairs,
Eda-A1/Edar/NF-kB up-regulates connective tissue growth
factor (CTGF) expression [25,35], while secondary hair
Current Biology Vol 19 No 3
R136
Table 2. Summary of the best defined molecular regulators of hair follicle
morphogenesis.
Hair Follicle
Morphogenesis
Step
Gene Product
Outer root sheath Sox9
Shh/Smo
Inner root sheath GATA3
Cutl1 (CDP)
BMPs/BMPR1a
Shh/Smo
Hair shaft
Notch1/Jagged/
Delta/RBP-Jk for IRS
fate maintenance
b-catenin, Wnt’s and Lef-1
VDR (Vitamin D receptor)
(only in postnatal hair cycle)*
BMPs/BMPR1a
Shh/Smo
msx1 and 2
FoxN1/Nude
HoxC13
Notch1/Jagged/Delta/RBP-Jk
(only in postnatal hair cycle)*
Polarity, shaping Shh (asymmetric, polarized
and bending
expression pattern
in hair matrix)
Igfbp5
Eda A1
Krox-20
FoxE1
Runx3
Sox18
Innervation
Pigmentation
Bulge region/
hair stem cell
maintenance
b-catenin
NCAM
FoxN1/Nude
SCF/c-kit
Notch
BMPs/BMPR1a
Lhx2
Sox9
NFATc1
p63
Tcf3 (w/o Wnt activity!)
Rac1
integrins a3b1 and a6b4
References
[82]
[106], and
references therein
[107]
[108]
[36–38]
[106], and
references therein
Reviewed in [52]
[23,24]
[109]
[36–38]
[106], and
references therein
[110]
[102]
Reviewed in [111]
Reviewed in [52]
[112]
[113]
Reviewed in [7]
[114]
[115]
[116]
[117]
[24]
[118]
[92]
[90]
Reviewed in [119]
Reviewed in [8,9]
Reviewed in [8]
[79,82]
[78]
Reviewed in [9]
[60]
Reviewed in [80]
Reviewed in [9]
Transcription factors in Italics.
placode development depends on Noggin [27]. However,
mice deficient in epidermal BMP activity have relatively
normal placode numbers, suggesting that inhibition of
epidermal BMP activity alone is insufficient to stimulate
hair follicle placode formation, and that BMP inhibition may
be most important within the developing placode in order
to allow for growth [36–38].
The regular pattern of hair follicle placodes may reflect the
Turing model of reaction–diffusion systems [32–34], as previously described for feather development [39]. Both, Wnt and
Dkks are secreted into the extracellular space and can therefore participate in such a reaction–diffusion system (Figure 2). Given the key role of Wnt in hair follicle fate induction
[21], its activity within and around the developing hair placode must be tightly controlled. Limiting Wnt activity may
also be important to avoid skin tumour formation, which
occurs in mice with overactive epidermal Wnt/b-catenin
signalling [40]. Due to its smaller molecular size, the Wnt
inhibitor Dkk4 could easily diffuse into placode surroundings, thereby inhibiting Wnt signalling in the interfollicular
epidermis proximal to the developing hair follicle placode,
while the larger Wnt molecules would remain within the placode [34]. Thus, moderate overexpression of the hair follicle
activator Wnt would increase hair follicle density, while
moderate overexpression of hair follicle inhibitor Dkk4 would
decrease hair follicle density [21,23,24,34].
Hair Follicle Cycling
The hair follicle undergoes regular cycles of involution and
regeneration throughout life. Once a first ‘test’ hair shaft
has been generated during continued postnatal hair follicle
morphogenesis, in mice, hair follicle cycling is initiated about
17 days post partum. At this time, hair follicles undergo rapid
organ involution (catagen; Figure 3). This first catagen lasts
two to three days, and is followed by the first phase of relative
quiescence (telogen; Figure 3). In mice, hair follicle morphogenesis proceeds throughout early postnatal life, which is
why it is routinely misinterpreted as ‘first anagen’. Instead,
the first real growth phase of the hair follicle cycle (anagen;
Figure 3) does not occur until 4 weeks after birth [41]. In anagen, the hair matrix keratinocytes, which represent transient
amplifying cells derived from epithelial hair follicle stem cells
in the bulge, proliferate intensively and then differentiate into
distinct epithelial hair lineages (Table 2) [2,8,13,41].
During catagen, the lower two-thirds of the hair follicle
rapidly regress, mainly by apoptosis of matrix, inner root
sheath and outer root sheath keratinocytes, while bulge
hair follicle stem cells escape apoptosis. Eventually, the
lower hair follicle becomes reduced to an epithelial strand,
bringing the dermal papilla into close proximity of the bulge
(Figure 3) [2,41]. In mice, the old hair shaft (club hair) normally
remains in its canal even when the new hair emerges through
the same orifice, and the telogen club hair can rest in its
socket during several cycles, thereby contributing to the
density of the coat. This leads to bulging of the outer root
sheath around the club (Figure 3). While old hair shafts can
be shed passively by mechanical forces, shedding may
mainly be an active process, termed exogen, the molecular
controls of which remain to be clarified [2].
Upon catagen completion, hair follicles enter a phase of
relative quiescence (telogen), lasting several days in the first
telogen and usually more than 3 weeks in the second telogen.
With each additional cycle telogen duration expands, and hair
follicle cycling slows down considerably in aging animals.
Moreover, while the initial waves of pelage hair follicle cycling
in mice are highly synchronized, patches of coordinated hair
follicle cycling will eventually form distinct hair cycle domains,
which become more scattered as the mouse ages [42]. In
contrast, in humans, synchronized fetal hair follicle cycling
becomes asynchronous soon after birth, when each hair
follicle starts to follow its own mosaic cycling pattern [3,11].
The molecular mechanisms that drive hair follicle cycling
remain obscure, although multiple molecular regulators
have been identified through mouse mutants with defects in
hair follicle cycling, and by characterizing gene expression
profiles of distinct murine hair cycle stages [2,11,43]. Mouse
mutants have demonstrated that Wnt/b-catenin, BMP antagonists (e.g. Noggin) and Shh act as anagen-inducing signals,
while FGF5 is a key inducer of catagen [2,3,11,44]. FGF5-deficient mice have a prolonged anagen phase resulting in an
angora hair phenotype [44]. In addition to FGF5, TGF-b1,
Review
R137
Permanent
Start of hair
follicle cycling
Stage 8
Stage 1
DC
SG
Stage 5
Stage 3
SC
Placode
Cycling
Epidermis
Catagen
APM
HS
Bulge
IRS cone
MC
DP
Regressing
epithelial
column
ge
n
Hair follicle morphogenesis
Ca
ta
Anagen VI
Anagen
SG
Telogen
Teloge
n
APM
Bulge
Bulge
Club hair
DP
Anagen IV
IRS
Anagen II
HS
ORS
Bulge
Bulb
New hair germ
DP
New hair
DP
Current Biology
Figure 3. Key stages of the hair cycle.
The hair cycle is divided into three phases: Anagen (growth phase), catagen (regression phase) and telogen (resting phase). Postnatal hair
morphogenesis leads to elongation of the follicle and production of the hair fiber, which emerges from the skin. Once the hair follicle has matured,
it enters the regression phase, during which the lower, cycling portion of the hair follicle is degraded. This process brings the dermal papilla into
close proximity of the bulge, where the hair stem cells (HSCs) reside. The molecular interaction between the HSCs and the dermal papilla is essential to form a new hair follicle. The proximity between bulge and dermal papilla is maintained throughout telogen, the resting phase. Only when
a critical concentration of hair growth activating signals is reached, anagen phase is entered and a new hair is regrown. The first postnatal
hair cycle is initiated and passed by all hair follicles at the same time point, while subsequent cycles are no longer synchronized. Stages 1–8
of embryonic hair development are depicted (upper left), demonstrating the continuous transition between hair follicle development and the first
postnatal hair cycle. APM: arrector pili muscle; DC, dermal condensate (green); DP: dermal papilla (green); HS: hair shaft (brown); IRS: inner root
sheath (blue); MC: melanocytes; ORS: outer root sheath; SC: sebocytes (yellow); SG: sebaceous gland.
interleukin-1b, the neurotrophins NT-3, NT-4 and BDNF,
BMP2/4 and TNF-a have been described to induce catagen
[2,11]. Conversely, insulin-like growth factor-1 (IGF-1),
hepatic growth factor (HGF), and vascular endothelial growth
factor (VEGF) are thought to be important for anagen maintenance [11,45]. Furthermore, the molecular crosstalk between
downstream effectors of TNF-a signalling and keratin17 (K17)
may be in part responsible for controlling catagen entry by
regulating the rate of apoptosis [45].
Additional molecules implicated in controlling anagen–
catagen transformation include the vitamin D receptor
(VDR), the transcriptional repressor Hairless and the retinoic
acid receptor [11,46–49]. Interestingly, Hairless interacts
with VDR to regulate transcription [50], and in mice lacking
these regulators, hair follicles disintegrate into epithelial
sacs and dermal cysts upon catagen entry [46–49]. The
concomitant detachment of the dermal papilla from the
hair follicle epithelium disrupts the essential interaction
between hair follicle stem cells and the inductive hair follicle
mesenchyme [46–49].
Although traditionally described as the resting phase of the
hair follicle cycle, telogen coincides with major changes
in gene activity [43]. Indeed, some regulatory proteins, like
the estrogen receptor, are markedly up-regulated in telogen
[51]. Therefore, telogen is not at all quiescent, and probably
represents a key stage in hair cycle control. This is supported
Current Biology Vol 19 No 3
R138
Stem cell
Activation
stab. β-catenin,
Wnts?
↑c-myc
Maintenance
LHX2, Sox9, low c-myc,
integrins α3β1 and α6β4.
Quiescence
BMPs, TCF3 and other
Wnt inhibitors, NFATc1
↑ BMP
Transient
amplifying cell
2–5 divisions.
↓ integrins and
hemidesmosomes
Hair follicle
Differentiation
Wnt/β-cat,
TGFβ,
Notch, BMPs,
Shh, etc.
↑ BMP
Figure 4. Schematic presentation of the
temporal interplay of the molecular players
in hair stem cell activation.
Upper panel: List of molecules required for
stem cell maintenance/quiescence, activation and differentiation. Lower panel:
Comparison between the relative amounts of
BMP (blue) and Wnt/b-catenin (orange)
activity needed for quiescence, activation
and differentiation of hair follicle stem cells.
For more details see main text.
and Wnt activation together with stabilization of b-catenin (Figure 4) [8–
10,40,57,58]. In addition, both pathways may temporally regulate the
activities of each other: During quies↓ BMP
Wnt/β-cat
W
nttWnt/β-cat
/ β -catt
↓
BMP
B
MP
cence, BMP may indirectly prevent
–
+
b-catenin stabilization [59]. However,
Quiescence
Differentiation HF
Activation
at anagen onset, increasing Wnt sigCurrent Biology
nalling may induce b-catenin stabilization and the local expression of BMP
by the recent discovery that telogen can be divided into inhibitors in the dermal papilla [8,10]. Nevertheless, it
a phase that is refractory to hair follicle growth stimuli and currently remains unexplained how Wnt signalling is
that is characterized by upregulation and activation of switched on.
During early anagen development, the bulge progressively
BMP2/4, and a competent phase in which bulge stem cells
become highly sensitive to anagen-inducing factors [42]. In moves away from the dermal papilla (Figure 3), and epithelial
the competent phase, BMP signalling is turned off while hair follicle stem cells re-adopt quiescence. However, the
Wnt/b-catenin signalling is turned on to reach its optimal stem cell progeny in the hair matrix (transient amplifying
activity in early anagen. Interestingly, there are cyclic changes cells) maintains active Wnt signalling and concomitant stabiin BMP2 and BMP4 expression in extrafollicular skin, namely lization of b-catenin throughout anagen. More distally in the
in subcutaneous adipocytes [42]. This extrafollicular system precortical hair matrix, these cells stop proliferating and
must interact with the autonomous, intrafollicular ‘hair cycle initiate terminal differentiation into the different lineages of
hair follicle epithelium (Figure 1D and Table 2). By now,
clock’ to regulate individual hair follicle cycles [11].
In telogen, the dermal papilla comes to rest immediately many molecular regulators of hair lineages have been
below the bulge, which allows direct interactions between discovered, such as GATA3, Cutl1 and BMPs for inner root
bulge stem cells and the dermal papilla. The dermal papilla sheath formation, Sox9 and SHH for outer root sheath formais essential for stem cell activation and initiation of a new tion, and Wnt/b-catenin, VDR, Notch, BMPs and Foxn1 for
hair cycle. Once a critical concentration of stem cell activa- the expression of selected hair shaft keratins and/or hair
tors has been achieved, anagen is initiated [11]. Despite the shaft development (Table 2). In contrast, TCF3 operates as
many morphological and molecular parallels between the a general inhibitor of all epithelial lineages [60].
Many important questions in hair cycle research remain
interactions of the bulge region with the dermal papilla and
the hair follicle placode with the dermal condensate during unanswered. For instance, it remains unknown how only
hair follicle development, there are also marked molecular a few selected stem cells are activated during each cycle
differences (Figure 3, Table 2). For example, some members and how the other stem cells are kept in a quiescent state.
of the TGF-b and nerve growth factor families have opposing And how exactly is the responsiveness of stem cells to Wnt
functions during hair follicle development and cycling: While regulated? The most important challenge, however, is to
both promote development, they stimulate regression (cata- dissect the molecular nature of the autonomous intrafollicugen) in mature follicles [11]. Other signals, like VDR, hairless lar oscillator system that regulates the cyclic transformation
and Notch, are dispensable for hair follicle development, of each hair follicle [11]. While many genes controlling epithelial hair follicle stem cell activity and hair follicle cycling have
but essential for anagen induction (Table 2) [48,52].
The molecular details of stem cell activation remain been identified, the intrafollicular clock seems to be
unknown. However, a critical threshold concentration of controlled by a more elementary molecular machinery, which
one or several activator molecules must be reached to may even incorporate differential ‘clock gene’ activities. This
trigger anagen onset, while inhibitors have to be switched hair cycle clock must not be confused with signals that arise
off. Some molecular players that control the balance from extrafollicular skin to alter the cycling of large groups of
between stem cell quiescence/maintenance and activation hair follicles in order to induce wave and domain pattern
have already been identified by gene expression profiling formation [42]. Mouse genetics and further hair cycle gene
of the hair cycle and the hair follicle compartment in mice expression profiling appear most promising approaches
and humans [15,43,53–56]. While stem cell quiescence towards elucidating the enigmatic ‘‘hair cycle clock’’
appears to be maintained by activation of BMP signalling [11,43]. A more detailed analysis of mice with greatly accelin combination with Wnt inhibition by TCF3 and DKKs, erated hair follicle cycling, such as fuzzy mice, which carry
stem cell activation is thought to require BMP inhibition a mutation in sgk3, may be a good start [61,62].
Review
R139
Hair Follicle Stem Cells
As a self-regenerating system, the hair follicle and its
connective tissue sheath are not only a rich source of epithelial, but also of melanocyte, mesenchymal and neural stem
cells [9,14,63–65]. Making use of their slow cycling, labelretaining experiments have located adult epithelial hair
follicle stem cells in the hair follicle bulge region of mice
and humans [14,63]. This led to the ‘bulge activation hypothesis’: At the onset of anagen, a subset of hair follicle stem
cells is activated and starts to divide. Their daughter cells
migrate to the base of the follicle where they start to proliferate and become transiently activated matrix cells. In vivo
labelling and transplantation studies confirmed the ability
of bulge stem cells to give rise to all cell lineages of the
mature hair follicle [66,67].
In accordance with this hypothesis, major inflammatory
damage of the bulge can result in permanent, cicatricial
alopecia [68,69]. Unless the skin is injured, bulge stem cells
exclusively contribute to hair follicle maintenance and
regeneration [70–73], although they are also capable of
generating sebaceous glands and the interfollicular epidermis [55,56]. Conversely, at least in mice, epithelial cells may
assume a hair follicle stem cell phenotype under certain
wounding conditions, which may lead to hair follicle neogenesis in adult skin [4].
Apart from their ability to generate hair follicles, sebaceous
glands and interfollicular epidermis, epithelial hair follicle
stem cells also hold a ‘dark side’: Their long life span
exposes them to multiple genetic mutations, and their quiescent character may facilitate retention of carcinogens, thus
rendering them more susceptible to tumour development,
such as basal cell carcinoma. [14].
Keratin 15 (K15) and CD34 are typical markers for rodent hair
follicle epithelial stem cells [14,74,75], and K15 has been used
to isolate putative murine bulge stem cells and to establish
their gene expression profile [54–56]. When compared with
epidermal basal layer stem cells, genes typically upregulated
in the bulge include stem cell markers such as c-kit ligand,
ephrin tyrosine kinase receptors and CD34, but also many
known bulge markers like the homeobox genes and transcription factors Barx2, Sox9, Lhx2, and the transcription factor
TCF3 [54–56]. As expected, down-regulated genes include
proliferation-associated proteins such as Ki67and Cdc25C.
Genes involved in Wnt pathway activation are largely
repressed in murine bulge stem cells, while the expression
of Wnt inhibitors such as Srfp1, Dab2, and TCF3 is increased
as compared to non-bulge keratinocytes [54–56,60]. This is
in line with the concept that Wnt signalling induces epithelial
hair follicle stem cells to differentiate and to adopt a hair fate
[22,58,60]. Hair follicle stem cell quiescence requires BMP
signalling [8,10]. In mice lacking BMPR1a, hair follicle stem
cells are continuously activated and start proliferating
aberrantly, resulting in the eventual loss of slow cycling
cells in these mice [36–38,76,77]. As expected, these mice
reveal increased and aberrant levels of Lef-1 and stabilized
b-catenin in the stem cell niche, suggesting that BMP signalling may be important for decelerating the cell cycle and
maintaining the hair follicle stem cell population by preventing activation of the Wnt pathway (Figure 4). In addition to
BMPs, stem cell quiescence appears to be regulated by
the Wnt inhibitor TCF3 and the calcium-dependent transcription factor NFATc1 [60,76,78].
Stem cell maintenance is ensured by slow cycling, and
controlled by low levels of c-myc and by the expression of
the transcription factors LHX2 and Sox9 (Figure 4) [79–82].
Conversely, activation of stem cells during the telogen–anagen transition requires BMP inhibition by BMP antagonists,
Wnts and stabilized b-catenin, as well as increased levels
of c-myc, and Runx1 (Figure 4) [8,10,83].
Distinct subpopulations of epithelial hair follicle stem cells
and their progeny are already present at the earliest stages of
hair follicle development prior to birth [79]. Sox9-positive
stem cells appear to be required for the postnatal formation
of a normal matrix, outer root sheath, bulge and sebaceous
gland [79,82]. By contrast, Lhx2-positive stem cells are
found in the early placode and germ, but disappear later in
hair follicle development. These cells may represent transient amplifying cells that participate in prenatal hair follicle
initiation and development [79].
In human hair follicles, characteristic hair stem cell
markers remain to be identified [64]. However, up-regulated
KRT15, KRT19 and CD200 expression, combined with the
absence of CD34, nestin, and connexin 43 expression may
indicate the presence of human bulge epithelial stem cells
[84]. Finally, transcriptional profiling studies of human bulge
cells have revealed similarities and important disparities
between mouse and human bulge cells [53]: Similar to mouse
hair stem cells, inhibitors of the Wnt signalling pathway and
CD200 are transcriptionally up-regulated, while the mouse
bulge stem cell marker CD34 is not expressed [14,64,84].
Hair Pigmentation
Hair shaft pigmentation serves multiple purposes, which
vary between species: skin protection against UV irradiation,
thermoregulation, camouflage and sexual signals. Furthermore, the hair pigment melanin, which is produced in hair
follicle melanocytes, is a potent free-radical scavenger.
Melanin production inside the metabolically highly active
anagen hair bulb may, therefore, help to buffer cell stress
induced by reactive oxygen species. In addition, the transfer
of melanin from melanocytes to keratinocytes may promote
differentiation of the melanin-receiving keratinocytes situated in the precortical hair matrix [85]. In contrast to the
continuous melanogenesis observed in epidermal melanocytes, follicular melanogenesis is a strictly anagen-coupled,
cyclic phenomenon. It is shut off very early during the anagen–catagen transition, beginning with the down-regulation
of key enzymes of melanogenesis, followed by hair follicle
melanocyte apoptosis [85].
Hair follicle melanocytes and their precursors reside in the
hair matrix and along the outer root sheath of anagen hair
follicles. However, production of hair pigment (black eumelanin and/or the reddish pheomelanin) only occurs in the
specialized hair follicle pigmentary unit, located above and
around the dermal papilla during anagen III–VI. Melanin
synthesis is confined to lysosome-related organelles, melanosomes, under the control of tyrosinase. In the precortical
matrix, these melanosomes are actively exported and transferred to the recipient hair shaft keratinocytes, resulting in
the formation of a pigmented hair shaft [85].
In mice, neural-crest derived melanoblasts populate the
hair follicle epithelium in defined developmental waves,
a process regulated by c-KIT and its ligand, stem cell factor
(SCF) [86]. The melanocytes and melanoblasts that come to
reside in the outer root sheath normally do not in engage in
pigment production, yet can replace lost epidermal melanocytes. The hair follicle also contains melanocyte stem cells,
which are located in the bulge and in the secondary hair
Current Biology Vol 19 No 3
R140
germ region (i.e. below the telogen club hair), where they
serve as a cell pool for the cyclic regeneration of the hair
follicle pigmentary unit [85]. Melanocyte stem cells are
needed for replacing the vast majority of differentiated,
melanotic hair follicle melanocytes that undergo apoptosis
during catagen [85,87]. Preservation of the hair follicle melanocyte stem cell pool and regulation of the sensitive balance
between maintenance and differentiation appears to depend
on the transcription factors Pax3 and Mitf [88,89].
The correct localization and activity of melanocytes within
different skin compartments is directed by paracrine signals.
In murine pelage hair follicles, these include SCF and hepatocyte growth factor [90,91]. Recently, expression of the forkhead family transcription factors, Foxn1, and activation of its
downstream target FGF2 in pigment-recipient keratinocytes
were identified as the major regulators in determining the
patterning of hair pigmentation [92]. Thus, hair pigmentation
patterning appears to depend on the melanin-receiving hair
follicle keratinocytes, which specifically attract hair follicle
melanocytes into their close proximity by FGF2 via Foxn1 [92].
Graying of hair (canities) is the direct result of a marked loss
in active melanocytes in the hair follicle pigmentary unit, and
usually begins between the mid-30s and the mid-40s. The
chief cause of graying has been attributed to a depletion of
the melanocyte stem cell reservoir. However, damage to
the hair follicle pigmentary unit by reactive oxygen species
probably also plays an important role in graying, independent
of, and in addition to its deleterious effects on hair follicle
melanocyte stem cells [85,93]. It is not clear yet, however,
why hair follicle melanocytes and their progenitors appear
to age faster than their epidermal counterparts.
regenerative medicine [6,64,95]. Beyond the topics covered
in this review, emerging areas in hair research — for
example, understanding the immune privilege of the hair
follicle bulb and bulge and the complex (neuro-)endocrine
activities of the hair follicle — may revolutionize our understanding of hair follicle biology in the near future [69,96,97].
Acknowledgments
Writing of this review was made possible in part by grants from the
Deutsche Forschungsgemeinschaft (DGF) to M.R.S. (GRK1029), R.S.U.
(SCHM 855/3-1) and R.P. (Pa 345/12-1).
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Conclusions and Perspectives
Proper functioning of the hair follicle comprises perfectly
coordinated principles of developmental, stem cell, and
tumour biology, tissue regeneration, and the control of cell
growth, migration, death, and differentiation. As such, the
hair follicle is an accessible and clinically relevant model.
From the biological point of view, further detailed studies
are needed to unravel the signalling cascades and crosstalk that lead to induction of hair follicle development and
subsequent morphogenesis. It will also be interesting to
further dissect the molecular differences between fetal hair
follicle induction and development and the hair follicle cycle.
From the clinical perspective, the key challenge will be to
translate the insights from hair follicle biology into treatments
for disorders of the human hair follicle, such as androgenetic
alopecia, telogen effluvium, alopecia areata, hirsutism, or
graying. This may be achieved by specifically targeting
some of the key molecular controls in hair follicle cycling
and melanogenesis, perhaps even to the point of de novo
induction of hair follicles in adult human skin [5,6]. The potent
hair growth stimulator cyclosporine A provides an intriguing
example for how links between classical immunopharmacology and epithelial stem cell biology may stimulate future ‘hair
drug’ development [78].
Strategies and concepts developed in studies on hair
follicle epithelial stem cells have already influenced adult
stem cell research in other tissues, such as the intestinal
epithelium [10,14,64,79,94]. Furthermore, the hair follicle
and its surrounding mesenchyme are now recognized as
potent sources for multipotent stem cell populations, raising
hopes that stem cells associated with adult human hair
follicles might soon become exploitable for uses in
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Paus, R., and Cotsarelis, G. (1999). The biology of hair follicles. N. Engl.
J. Med. 341, 491–497.
Stenn, K.S., and Paus, R. (2001). Controls of hair follicle cycling. Physiol
Rev. 81, 449–494.
Cotsarelis, G., and Botchkarev, V.A. (2008). Biology of hair follicles. In
Fitzpatrick’s Dermatology in General Medicine, K. Wollf, L.A. Goldsmith,
S.I. Katz, B.A. Gilchrest, A.S. Paller, and D.J. Leffell, eds. (New York:
McGraw Hill), pp. 739–749.
Ito, M., Yang, Z., Andl, T., Cui, C., Kim, N., Millar, S.E., and Cotsarelis, G.
(2007). Wnt-dependent de novo hair follicle regeneration in adult mouse
skin after wounding. Nature 447, 316–320.
Reynolds, A.J., Lawrence, C., Cserhalmi-Friedman, P.B., Christiano, A.M.,
and Jahoda, C.A. (1999). Trans-gender induction of hair follicles. Nature
402, 33–34.
Chuong, C.M., Cotsarelis, G., and Stenn, K. (2007). Defining hair follicles in
the age of stem cell bioengineering. J. Invest Dermatol. 127, 2098–2100.
Schmidt-Ullrich, R., and Paus, R. (2005). Molecular principles of hair follicle
induction and morphogenesis. Bioessays 27, 247–261.
Fuchs, E. (2007). Scratching the surface of skin development. Nature 445,
834–842.
Fuchs, E. (2008). Skin stem cells, rising to the surface. J. Cell Biol. 180,
273–284.
Fuchs, E., and Horsley, V. (2008). More than one way to skin. Genes Dev. 22,
976–985.
Paus, R., and Foitzik, K. (2004). In search of the ‘‘hair cycle clock’’: a guided
tour. Differentiation 72, 489–511.
Nakamura, M., Sundberg, J.P., and Paus, R. (2001). Mutant laboratory mice
with abnormalities in hair follicle morphogenesis, cycling, and/or structure:
annotated tables. Exp. Dermatol. 10, 369–390.
Legue, E., and Nicolas, J.F. (2005). Hair follicle renewal: organization of
stem cells in the matrix and the role of stereotyped lineages and behaviors.
Development 132, 4143–4154.
Cotsarelis, G. (2006). Epithelial stem cells: a folliculocentric view. J. Invest
Dermatol. 126, 1459–1468.
Rendl, M., Lewis, L., and Fuchs, E. (2005). Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS. Biol. 3, e331.
Mikkola, M.L. (2007). Genetic basis of skin appendage development.
Semin. Cell Dev. Biol. 18, 225–236.
Wu, P., Hou, L., Plikus, M., Hughes, M., Scehnet, J., Suksaweang, S.,
Widelitz, R., Jiang, T.X., and Chuong, C.M. (2004). Evo-Devo of amniote
integuments and appendages. Int. J. Dev. Biol. 48, 249–270.
Wu, G., Deng, Z., Fan, X., Ma, Z., Sun, Y., Ma, D., Wu, J., Shi, J., and Jin, Y.
(2008). Odontogenic potential of mesenchymal cells from hair follicle
dermal papilla. Stem Cells Dev. epub ahead of print.
Atit, R., Sgaier, S.K., Mohamed, O.A., Taketo, M.M., Dufort, D., Joyner, A.L.,
Niswander, L., and Conlon, R.A. (2006). Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev.
Biol. 296, 164–176.
Paus, R., Muller-Rover, S., Van, D.V., Maurer, M., Eichmuller, S., Ling, G.,
Hofmann, U., Foitzik, K., Mecklenburg, L., and Handjiski, B. (1999). A
comprehensive guide for the recognition and classification of distinct
stages of hair follicle morphogenesis. J. Invest Dermatol. 113, 523–532.
Andl, T., Reddy, S.T., Gaddapara, T., and Millar, S.E. (2002). WNT signals
are required for the initiation of hair follicle development. Dev. Cell 2,
643–653.
Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G., and Birchmeier, W.
(2001). beta-Catenin controls hair follicle morphogenesis and stem cell
differentiation in the skin. Cell 105, 533–545.
Narhi, K., Jarvinen, E., Birchmeier, W., Taketo, M.M., Mikkola, M.L., and
Thesleff, I. (2008). Sustained epithelial beta-catenin activity induces precocious hair development but disrupts hair follicle down-growth and hair
shaft formation. Development 135, 1019–1028.
Zhang, Y., Andl, T., Yang, S.H., Teta, M., Liu, F., Seykora, J.T., Tobias, J.W.,
Piccolo, S., Schmidt-Ullrich, R., Nagy, A., et al. (2008). Activation of
{beta}-catenin signaling programs embryonic epidermis to hair follicle
fate. Development 135, 2161–2172.
Review
R141
25.
Pummila, M., Fliniaux, I., Jaatinen, R., James, M.J., Laurikkala, J.,
Schneider, P., Thesleff, I., and Mikkola, M.L. (2007). Ectodysplasin has
a dual role in ectodermal organogenesis: inhibition of Bmp activity and
induction of Shh expression. Development 134, 117–125.
49.
Potter, G.B., Beaudoin, G.M., III, DeRenzo, C.L., Zarach, J.M., Chen, S.H.,
and Thompson, C.C. (2001). The hairless gene mutated in congenital hair
loss disorders encodes a novel nuclear receptor corepressor. Genes
Dev. 15, 2687–2701.
26.
Jamora, C., DasGupta, R., Kocieniewski, P., and Fuchs, E. (2003). Links
between signal transduction, transcription and adhesion in epithelial bud
development. Nature 422, 317–322.
50.
27.
Botchkarev, V.A., Botchkareva, N.V., Sharov, A.A., Funa, K., Huber, O., and
Gilchrest, B.A. (2002). Modulation of BMP signaling by noggin is required
for induction of the secondary (nontylotrich) hair follicles. J. Invest Dermatol. 118, 3–10.
Hsieh, J.C., Sisk, J.M., Jurutka, P.W., Haussler, C.A., Slater, S.A., Haussler,
M.R., and Thompson, C.C. (2003). Physical and functional interaction
between the vitamin D receptor and hairless corepressor, two proteins
required for hair cycling. J. Biol. Chem. 278, 38665–38674.
51.
Ohnemus, U., Uenalan, M., Inzunza, J., Gustafsson, J.A., and Paus, R.
(2006). The hair follicle as an estrogen target and source. Endocr. Rev.
27, 677–706.
52.
Watt, F.M., Estrach, S., and Ambler, C.A. (2008). Epidermal Notch signalling: differentiation, cancer and adhesion. Curr. Opin. Cell Biol. 20, 171–179.
53.
Ohyama, M., Terunuma, A., Tock, C.L., Radonovich, M.F., Pise-Masison,
C.A., Hopping, S.B., Brady, J.N., Udey, M.C., and Vogel, J.C. (2006). Characterization and isolation of stem cell-enriched human hair follicle bulge
cells. J. Clin. Invest 116, 249–260.
54.
Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W.E., Rendl, M., and
Fuchs, E. (2004). Defining the epithelial stem cell niche in skin. Science 303,
359–363.
55.
Morris, R.J., Liu, Y., Marles, L., Yang, Z., Trempus, C., Li, S., Lin, J.S.,
Sawicki, J.A., and Cotsarelis, G. (2004). Capturing and profiling adult hair
follicle stem cells. Nat. Biotechnol. 22, 411–417.
56.
Blanpain, C., Lowry, W.E., Geoghegan, A., Polak, L., and Fuchs, E. (2004).
Self-renewal, multipotency, and the existence of two cell populations
within an epithelial stem cell niche. Cell 118, 635–648.
57.
Lo, C.C., Prowse, D.M., and Watt, F.M. (2004). Transient activation of betacatenin signalling in adult mouse epidermis is sufficient to induce new hair
follicles but continuous activation is required to maintain hair follicle
tumours. Development 131, 1787–1799.
58.
Van Mater, D., Kolligs, F.T., Dlugosz, A.A., and Fearon, E.R. (2003). Transient activation of beta -catenin signaling in cutaneous keratinocytes is
sufficient to trigger the active growth phase of the hair cycle in mice. Genes
Dev. 17, 1219–1224.
59.
Fukumoto, S., Hsieh, C.M., Maemura, K., Layne, M.D., Yet, S.F., Lee, K.H.,
Matsui, T., Rosenzweig, A., Taylor, W.G., Rubin, J.S., et al. (2001). Akt
participation in the Wnt signaling pathway through Dishevelled. J. Biol.
Chem. 276, 17479–17483.
60.
Nguyen, H., Rendl, M., and Fuchs, E. (2006). Tcf3 governs stem cell features
and represses cell fate determination in skin. Cell 127, 171–183.
61.
Mecklenburg, L., Tobin, D.J., Cirlan, M.V., Craciun, C., and Paus, R. (2005).
Premature termination of hair follicle morphogenesis and accelerated hair
follicle cycling in Iasi congenital atrichia (fzica) mice points to fuzzy as
a key element of hair cycle control. Exp. Dermatol. 14, 561–570.
62.
Campagna, D.R., Custodio, A.O., Antiochos, B.B., Cirlan, M.V., and
Fleming, M.D. (2008). Mutations in the serum/glucocorticoid regulated
kinase 3 (Sgk3) are responsible for the mouse fuzzy (fz) hair phenotype.
J. Invest. Dermatol. 128, 730–732.
63.
Cotsarelis, G., Sun, T.T., and Lavker, R.M. (1990). Label-retaining cells
reside in the bulge area of pilosebaceous unit: implications for follicular
stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329–1337.
64.
Tiede, S., Kloepper, J.E., Bodo, E., Tiwari, S., Kruse, C., and Paus, R. (2007).
Hair follicle stem cells: walking the maze. Eur. J. Cell Biol. 86, 355–376.
65.
Nishimura, E.K., Jordan, S.A., Oshima, H., Yoshida, H., Osawa, M., Moriyama, M., Jackson, I.J., Barrandon, Y., Miyachi, Y., and Nishikawa, S.
(2002). Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416, 854–860.
66.
Oshima, H., Rochat, A., Kedzia, C., Kobayashi, K., and Barrandon, Y. (2001).
Morphogenesis and renewal of hair follicles from adult multipotent stem
cells. Cell 104, 233–245.
28.
29.
30.
Botchkarev, V.A., Botchkareva, N.V., Roth, W., Nakamura, M., Chen, L.H.,
Herzog, W., Lindner, G., McMahon, J.A., Peters, C., Lauster, R., et al.
(1999). Noggin is a mesenchymally derived stimulator of hair-follicle induction. Nat. Cell Biol. 1, 158–164.
Schmidt-Ullrich, R., Tobin, D.J., Lenhard, D., Schneider, P., Paus, R., and
Scheidereit, C. (2006). NF-kappaB transmits Eda A1/EdaR signalling to
activate Shh and cyclin D1 expression, and controls post-initiation hair
placode down growth. Development 133, 1045–1057.
Chiang, C., Swan, R.Z., Grachtchouk, M., Bolinger, M., Litingtung, Y.,
Robertson, E.K., Cooper, M.K., Gaffield, W., Westphal, H., Beachy, P.A.,
et al. (1999). Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9.
31.
St Jacques, B., Dassule, H.R., Karavanova, I., Botchkarev, V.A., Li, J., Danielian, P.S., McMahon, J.A., Lewis, P.M., Paus, R., and McMahon, A.P.
(1998). Sonic hedgehog signaling is essential for hair development. Curr.
Biol. 8, 1058–1068.
32.
Stark, J., Andl, T., and Millar, S.E. (2007). Hairy math: insights into hairfollicle spacing and orientation. Cell 128, 17–20.
33.
Maini, P.K., Baker, R.E., and Chuong, C.M. (2006). Developmental biology.
The Turing model comes of molecular age. Science 314, 1397–1398.
34.
Sick, S., Reinker, S., Timmer, J., and Schlake, T. (2006). WNT and DKK
determine hair follicle spacing through a reaction-diffusion mechanism.
Science 314, 1447–1450.
35.
Mou, C., Jackson, B., Schneider, P., Overbeek, P.A., and Headon, D.J.
(2006). Generation of the primary hair follicle pattern. Proc. Natl. Acad.
Sci. USA 103, 9075–9080.
36.
Andl, T., Ahn, K., Kairo, A., Chu, E.Y., Wine-Lee, L., Reddy, S.T., Croft, N.J.,
Cebra-Thomas, J.A., Metzger, D., Chambon, P., et al. (2004). Epithelial
Bmpr1a regulates differentiation and proliferation in postnatal hair
follicles and is essential for tooth development. Development 131, 2257–
2268.
37.
Yuhki, M., Yamada, M., Kawano, M., Iwasato, T., Itohara, S., Yoshida, H.,
Ogawa, M., and Mishina, Y. (2004). BMPR1A signaling is necessary for
hair follicle cycling and hair shaft differentiation in mice. Development
131, 1825–1833.
38.
Kobielak, K., Pasolli, H.A., Alonso, L., Polak, L., and Fuchs, E. (2003).
Defining BMP functions in the hair follicle by conditional ablation of BMP
receptor IA. J. Cell Biol. 163, 609–623.
39.
Jiang, T.X., Jung, H.S., Widelitz, R.B., and Chuong, C.M. (1999). Selforganization of periodic patterns by dissociated feather mesenchymal cells
and the regulation of size, number and spacing of primordia. Development
126, 4997–5009.
40.
Gat, U., DasGupta, R., Degenstein, L., and Fuchs, E. (1998). De Novo hair
follicle morphogenesis and hair tumors in mice expressing a truncated
beta-catenin in skin. Cell 95, 605–614.
41.
Muller-Rover, S., Handjiski, B., Van, D.V., Eichmuller, S., Foitzik, K., McKay,
I.A., Stenn, K.S., and Paus, R. (2001). A comprehensive guide for the
accurate classification of murine hair follicles in distinct hair cycle stages.
J. Invest Dermatol. 117, 3–15.
42.
Plikus, M.V., Mayer, J.A., de la, C.D., Baker, R.E., Maini, P.K., Maxson, R.,
and Chuong, C.M. (2008). Cyclic dermal BMP signalling regulates stem
cell activation during hair regeneration. Nature 451, 340–344.
67.
Taylor, G., Lehrer, M.S., Jensen, P.J., Sun, T.T., and Lavker, R.M. (2000).
Involvement of follicular stem cells in forming not only the follicle but also
the epidermis. Cell 102, 451–461.
43.
Lin, K.K., Chudova, D., Hatfield, G.W., Smyth, P., and Andersen, B. (2004).
Identification of hair cycle-associated genes from time-course gene
expression profile data by using replicate variance. Proc. Natl. Acad. Sci.
USA 101, 15955–15960.
68.
Mobini, N., Tam, S., and Kamino, H. (2005). Possible role of the bulge region
in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris
as the prototype. J. Cutan. Pathol 32, 675–679.
69.
44.
Hebert, J.M., Rosenquist, T., Gotz, J., and Martin, G.R. (1994). FGF5 as
a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78, 1017–1025.
Harries, M.J., Meyer, K.C., and Paus, R. (2007). Hair loss as a result of
cutaneous autoimmunity: Frontiers in the immunopathogenesis of primary
cicatricial alopecia. Autoimmun. Rev., in press (DOI:10.1016/j.autrev.
2008.09.003).
45.
Tong, X., and Coulombe, P.A. (2006). Keratin 17 modulates hair follicle
cycling in a TNFalpha-dependent fashion. Genes Dev. 20, 1353–1364.
70.
46.
Bikle, D.D., Elalieh, H., Chang, S., Xie, Z., and Sundberg, J.P. (2006). Development and progression of alopecia in the vitamin D receptor null mouse.
J. Cell Physiol. 207, 340–353.
Levy, V., Lindon, C., Zheng, Y., Harfe, B.D., and Morgan, B.A. (2007).
Epidermal stem cells arise from the hair follicle after wounding. FASEB J.
21, 1358–1366.
71.
Panteleyev, A.A., Van, D.V., Rosenbach, T., Muller-Rover, S., Sokolov, V.E.,
and Paus, R. (1998). Towards defining the pathogenesis of the hairless
phenotype. J. Invest. Dermatol. 110, 902–907.
Levy, V., Lindon, C., Harfe, B.D., and Morgan, B.A. (2005). Distinct stem cell
populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9,
855–861.
72.
Ito, M., Liu, Y., Yang, Z., Nguyen, J., Liang, F., Morris, R.J., and Cotsarelis,
G. (2005). Stem cells in the hair follicle bulge contribute to wound repair but
not to homeostasis of the epidermis. Nat. Med. 11, 1351–1354.
73.
Ghazizadeh, S., and Taichman, L.B. (2001). Multiple classes of stem cells in
cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 20,
1215–1222.
47.
48.
Palmer, H.G., Martinez, D., Carmeliet, G., and Watt, F.M. (2008). The vitamin
D receptor is required for mouse hair cycle progression but not for maintenance of the epidermal stem cell compartment. J. Invest Dermatol. 128,
2113–2117.
Current Biology Vol 19 No 3
R142
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
Liu, Y., Lyle, S., Yang, Z., and Cotsarelis, G. (2003). Keratin 15 promoter
targets putative epithelial stem cells in the hair follicle bulge. J. Invest.
Dermatol. 121, 963–968.
Trempus, C.S., Morris, R.J., Bortner, C.D., Cotsarelis, G., Faircloth, R.S.,
Reece, J.M., and Tennant, R.W. (2003). Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34.
J. Invest. Dermatol. 120, 501–511.
Kobielak, K., Stokes, N., de la, C.J., Polak, L., and Fuchs, E. (2007). Loss of
a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc. Natl. Acad. Sci. USA 104, 10063–10068.
Zhang, J., He, X.C., Tong, W.G., Johnson, T., Wiedemann, L.M., Mishina, Y.,
Feng, J.Q., and Li, L. (2006). Bone morphogenetic protein signaling inhibits
hair follicle anagen induction by restricting epithelial stem/progenitor cell
activation and expansion. Stem Cells 24, 2826–2839.
Horsley, V., Aliprantis, A.O., Polak, L., Glimcher, L.H., and Fuchs, E. (2008).
NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132,
299–310.
Nowak, J.A., Polak, L., Pasolli, H.A., and Fuchs, E. (2008). Hair follicle stem
cells are specified and function in early skin morphogenesis. Cell Stem Cell
3, 33–43.
Watt, F.M., Frye, M., and Benitah, S.A. (2008). MYC in mammalian
epidermis: how can an oncogene stimulate differentiation? Nat. Rev.
Cancer 8, 234–242.
Rhee, H., Polak, L., and Fuchs, E. (2006). Lhx2 maintains stem cell character
in hair follicles. Science 312, 1946–1949.
Vidal, V.P., Chaboissier, M.C., Lutzkendorf, S., Cotsarelis, G., Mill, P., Hui,
C.C., Ortonne, N., Ortonne, J.P., and Schedl, A. (2005). Sox9 is essential
for outer root sheath differentiation and the formation of the hair stem
cell compartment. Curr. Biol. 15, 1340–1351.
Osorio, K.M., Lee, S.E., McDermitt, D.J., Waghmare, S.K., Zhang, Y.V.,
Woo, H.N., and Tumbar, T. (2008). Runx1 modulates developmental, but
not injury-driven, hair follicle stem cell activation. Development 135,
1059–1068.
Kloepper, J.E., Tiede, S., Brinckmann, J., Reinhardt, D.P., Meyer, W.,
Faessler, R., and Paus, R. (2008). Immunophenotyping of the human bulge
region: the quest to define useful in situ markers for human epithelial hair
follicle stem cells and their niche. Exp. Dermatol. 17, 592–609.
Slominski, A., Wortsman, J., Plonka, P.M., Schallreuter, K.U., Paus, R., and
Tobin, D.J. (2005). Hair follicle pigmentation. J. Invest Dermatol. 124, 13–21.
Peters, E.M., Tobin, D.J., Botchkareva, N., Maurer, M., and Paus, R. (2002).
Migration of melanoblasts into the developing murine hair follicle is
accompanied by transient c-Kit expression. J. Histochem. Cytochem. 50,
751–766.
Tobin, D.J., Hagen, E., Botchkarev, V.A., and Paus, R. (1998). Do hair bulb
melanocytes undergo apoptosis during hair follicle regression (catagen)?
J. Invest. Dermatol. 111, 941–947.
Nishimura, E.K., Granter, S.R., and Fisher, D.E. (2005). Mechanisms of hair
graying: incomplete melanocyte stem cell maintenance in the niche.
Science 307, 720–724.
Steingrimsson, E., Copeland, N.G., and Jenkins, N.A. (2005). Melanocyte
stem cell maintenance and hair graying. Cell 121, 9–12.
Botchkareva, N.V., Khlgatian, M., Longley, B.J., Botchkarev, V.A., and
Gilchrest, B.A. (2001). SCF/c-kit signaling is required for cyclic regeneration
of the hair pigmentation unit. FASEB J. 15, 645–658.
Lindner, G., Menrad, A., Gherardi, E., Merlino, G., Welker, P., Handjiski, B.,
Roloff, B., and Paus, R. (2000). Involvement of hepatocyte growth factor/
scatter factor and met receptor signaling in hair follicle morphogenesis
and cycling. FASEB J. 14, 319–332.
Weiner, L., Han, R., Scicchitano, B.M., Li, J., Hasegawa, K., Grossi, M., Lee,
D., and Brissette, J.L. (2007). Dedicated epithelial recipient cells determine
pigmentation patterns. Cell 130, 932–942.
Spatz, K.R., Overall, R., Klapp, B.F., Arck, P.C., and Peters, E.M. (2008).
Increased melanocyte apoptosis under stress-mediator Substance
P–elucidating pathways involved in stress-induced premature graying.
Exp. Dermatol. 17, 632.
Barker, N., and Clevers, H. (2007). Tracking down the stem cells of the
intestine: strategies to identify adult stem cells. Gastroenterology 133,
1755–1760.
Biernaskie, J., Sparling, J.S., Liu, J., Shannon, C.P., Plemel, J.R., Xie, Y.,
Miller, F.D., and Tetzlaff, W. (2007). Skin-derived precursors generate
myelinating Schwann cells that promote remyelination and functional
recovery after contusion spinal cord injury. J. Neurosci. 27, 9545–9559.
Paus, R., Nickoloff, B.J., and Ito, T. (2005). A ‘hairy’ privilege. Trends Immunol. 26, 32–40.
Paus, R., Arck, P., and Tiede, S. (2008). (Neuro-)endocrinology of epithelial
hair follicle stem cells. Mol. Cell Endocrinol. 288, 38–51.
Pennisi, D., Gardner, J., Chambers, D., Hosking, B., Peters, J., Muscat, G.,
Abbott, C., and Koopman, P. (2000). Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice. Nat. Genet. 24, 434–437.
Srivastava, A.K., Pispa, J., Hartung, A.J., Du, Y., Ezer, S., Jenks, T.,
Shimada, T., Pekkanen, M., Mikkola, M.L., Ko, M.S., et al. (1997). The Tabby
phenotype is caused by mutation in a mouse homologue of the EDA gene
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains. Proc. Natl. Acad. Sci. USA 94,
13069–13074.
Luetteke, N.C., Phillips, H.K., Qiu, T.H., Copeland, N.G., Earp, H.S., Jenkins,
N.A., and Lee, D.C. (1994). The mouse waved-2 phenotype results from a
point mutation in the EGF receptor tyrosine kinase. Genes Dev. 8, 399–413.
Stoye, J.P., Fenner, S., Greenoak, G.E., Moran, C., and Coffin, J.M. (1988).
Role of endogenous retroviruses as mutagens: the hairless mutation of
mice. Cell 54, 383–391.
Mecklenburg, L., Nakamura, M., Sundberg, J.P., and Paus, R. (2001). The
nude mouse skin phenotype: the role of Foxn1 in hair follicle development
and cycling. Exp. Mol. Pathol. 71, 171–178.
Koch, P.J., Mahoney, M.G., Ishikawa, H., Pulkkinen, L., Uitto, J., Shultz, L.,
Murphy, G.F., Whitaker-Menezes, D., and Stanley, J.R. (1997). Targeted
disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice
causes loss of keratinocyte cell adhesion with a phenotype similar to
pemphigus vulgaris. J. Cell Biol. 137, 1091–1102.
Montagutelli, X., Lalouette, A., Boulouis, H.J., Guenet, J.L., and Sundberg,
J.P. (1997). Vesicle formation and follicular root sheath separation in mice
homozygous for deleterious alleles at the balding (bal) locus. J. Invest
Dermatol. 109, 324–328.
Baynash, A.G., Hosoda, K., Giaid, A., Richardson, J.A., Emoto, N., Hammer,
R.E., and Yanagisawa, M. (1994). Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and
enteric neurons. Cell 79, 1277–1285.
Gritli-Linde, A., Hallberg, K., Harfe, B.D., Reyahi, A., Kannius-Janson, M.,
Nilsson, J., Cobourne, M.T., Sharpe, P.T., McMahon, A.P., and Linde, A.
(2007). Abnormal hair development and apparent follicular transformation
to mammary gland in the absence of hedgehog signaling. Dev. Cell 12,
99–112.
Kaufman, C.K., Zhou, P., Pasolli, H.A., Rendl, M., Bolotin, D., Lim, K.C.,
Dai, X., Alegre, M.L., and Fuchs, E. (2003). GATA-3: an unexpected regulator
of cell lineage determination in skin. Genes Dev. 17, 2108–2122.
Ellis, T., Gambardella, L., Horcher, M., Tschanz, S., Capol, J., Bertram, P.,
Jochum, W., Barrandon, Y., and Busslinger, M. (2001). The transcriptional
repressor CDP (Cutl1) is essential for epithelial cell differentiation of the
lung and the hair follicle. Genes Dev. 15, 2307–2319.
Palmer, H.G., Anjos-Afonso, F., Carmeliet, G., Takeda, H., and Watt, F.M.
(2008). The vitamin D receptor is a Wnt effector that controls hair follicle
differentiation and specifies tumor type in adult epidermis. PLoS ONE 3,
e1483.
Ma, L., Liu, J., Wu, T., Plikus, M., Jiang, T.X., Bi, Q., Liu, Y.H., Muller-Rover,
S., Peters, H., Sundberg, J.P., et al. (2003). ‘Cyclic alopecia’ in Msx2
mutants: defects in hair cycling and hair shaft differentiation. Development
130, 379–389.
Awgulewitsch, A. (2003). Hox in hair growth and development. Naturwissenschaften 90, 193–211.
Hammerschmidt, B., and Schlake, T. (2007). Localization of Shh expression
by Wnt and Eda affects axial polarity and shape of hairs. Dev. Biol. 305,
246–261.
Schlake, T. (2005). Segmental Igfbp5 expression is specifically associated
with the bent structure of zigzag hairs. Mech. Dev. 122, 988–997.
Schlake, T. (2006). Krox20, a novel candidate for the regulatory hierarchy
that controls hair shaft bending. Mech. Dev. 123, 641–648.
Brancaccio, A., Minichiello, A., Grachtchouk, M., Antonini, D., Sheng, H.,
Parlato, R., Dathan, N., Dlugosz, A.A., and Missero, C. (2004). Requirement
of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair
follicle morphogenesis. Hum. Mol. Genet. 13, 2595–2606.
Raveh, E., Cohen, S., Levanon, D., Groner, Y., and Gat, U. (2005). Runx3 is
involved in hair shape determination. Dev. Dyn. 233, 1478–1487.
Pennisi, D., Bowles, J., Nagy, A., Muscat, G., and Koopman, P. (2000). Mice
null for sox18 are viable and display a mild coat defect. Mol. Cell Biol. 20,
9331–9336.
Botchkarev, V.A., Eichmuller, S., Johansson, O., and Paus, R. (1997). Hair
cycle-dependent plasticity of skin and hair follicle innervation in normal
murine skin. J. Comp. Neurol. 386, 379–395.
Schouwey, K., and Beermann, F. (2008). The Notch pathway: hair graying
and pigment cell homeostasis. Histol. Histopathol. 23, 609–619.
