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Molecular
mediators of hair follicle embryogenesis
Identification
of the molecular pathways controlling differentiation and proliferation
in mammalian hair follicles provides the crucial
link to understanding the regulation of normal hair growth, the
basis of hereditary hair loss diseases, and the origin of follicle-based
tumors. The discovery that mammalian counterparts (homologs) of
genes important for normal Drosophila (fruit fly) development
also affect hair follicle development has opened up new vistas
in hair biology research. Homeobox (hox), hedgehog (hh), patched
(ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch
1 and armadillo/B-catenin genes are all critical for hair follicle
and vertebrate development in general. Because these genes were
all first discovered in Drosophila, most of the names assigned
to them describe the peculiar appearance (phenotype) of the corresponding
fly mutants.
Researchers have identified many of the regulatory molecules
important for the formation of the hair follicle, but how they
interact to generate hair follicle is not fully understood. One
of the earliest molecular pathways activated during hair follicle
development is the ß-catenin pathway, which is a downstream
mediator of WNT signaling. Products of the WNT gene family are
secreted glycoproteins that regulate cell proliferation, migration
and specification of cell fate in the embryo and adult. WNT proteins
are classified according to their ability to promote stabilization
of ß-catenin in the cytoplasm. The ß-catenin-dependent
WNT pathway signals through cytoplasmic stabilization and accumulation
of ß-catenin in the nucleus to activate gene transcription.
At this stage in our understanding of hair follicle embryogenesis,
WNT gene coded proteins are the first precuts known to be involved
in hair follicle development, but it is possible there is an even
earlier gene coded, signaling mechanism that activates hair follicle
development and promotes WNT gene signaling.
Normally, the ß-catenin pathway is inactive in the adult
epidermis. Expression of stabilized ß-catenin in the epidermis
of transgenic mice resulted in hair follicle morphogenesis demonstrating
its importance in hair follicle development. The hair follicles
formed complete with sebaceous glands and dermal papilla, but
also ultimately led to hair follicle tumors. Conversely, when ß-catenin
expression was ablated in the epidermis, hair follicle morphogenesis
was blocked. This remarkable finding through animal research could
eventually have therapeutic implications.
As well as a role in hair follicle induction, WNT signaling seems
to participate in the induction of hair shaft differentiation.
The pathway is specifically activated in precortex cells at the
base of the hair shaft, and binding sites for the transcription
factor Lef1, which mediates transcriptional responses to WNT signaling,
are found in the promoter regions of many hair keratin genes.
Members of the bone morphogenetic protein (BMP) signaling have
been implicated in the regulation of both proliferation and differentiation
in the hair follicle. BMP2 is expressed in the embryonic ectoderm,
but then localizes to the early hair follicle placode and underlying
mesenchyme. BMP4 is expressed in the early dermal condensate.
Research results show that BMPs are a key component of the signaling
network controlling hair development and are required to induce
the genetic program regulating hair shaft differentiation in the
anagen hair follicle.
The regulation of hair follicle development by the TNF family
member ectodysplasin, and its receptor, EDAR, has also been studied
extensively. Mutations in the X-linked EDA gene cause Anhidrotic
Ectodermal Dysplasia (EDA), a syndrome associated with decreased
numbers of hair follicles, and defects of the teeth and sweat
glands. The EDAR gene is required for expression of BMP4, as well
as Sonic hedgehog (SHH), indicating that EDAR acts very early
in follicular morphogenesis, and is required both for promoting
the hair follicle placode and for lateral inhibition of placode
fate in surrounding cells. Inhibitors of BMP action, such as Noggin,
are also important for normal hair follicle development. Mice
lacking Noggin have fewer hair follicles than normal and retarded
follicular development.
Hair follicle development and hair formation involve the coordinated
differentiation of several different cell types in which Notch
pathway appears to have a role. Notch-1 is expressed in ectodermal-derived
cells of the follicle, in the inner cells of the embryonic placode
and the follicle bulb, and in the suprabasal cells of the mature
outer root sheath. Delta-1, one of the three ligands is only expressed
during embryonic follicle development and is exclusive to the
mesenchymal cells of the pre-papilla located beneath the follicle
placode, and appears to promote and accelerate placode formation,
while suppressing placode formation in surrounding cells. Other
ligands, Serrate 1 and Serrate 2, are expressed in matrix cells
destined to form the inner root sheath and hair shaft.
Sonic hedgehog (SHH) signaling plays a critical role in hair
follicle development, but how it controls these processes remains
unclear. Skin from mice lacking SHH have extremely effete hair
follicles with poorly developed dermal papillae, suggesting that
SHH controls follicular proliferation, and follicle size.
Mediation of hair follicle distribution
Primitive hair germs, which are observed as a focal crowding
of basal-cell nuclei in the fetal epidermis first appear in the
regions of the upper lip, eyebrows, and chin. All further primary
follicle germs begin to develop over the surface of the body during
the fourth month of gestation. As the fetus grows, new primary
germs form among the existing ones, and secondary germs develop
in such an orientation to the primary germs so as to form new
follicles in groups of two, three or four (called follicular units).
This results in hairs being arranged in patterns, keeping relatively
constant distances from their neighbors, and having a uniform
regional slant.
The mechanism that regulates the distribution of hair follicles
and their clustering is very poorly understood. However, it is
presumed that the characteristic distribution of hair follicles
over the body is probably determined in part by genes called homeobox
genes. Homeobox genes are pattern genes that establish the body
plan and position of organs during embryonic development. Although
it has been established that several homeobox genes are expressed
during murine skin development, there is no definitive information
about developmental expression of these genes in human skin. In
adult mice, homeobox gene expression reappears in hair follicles,
and serves to maintain normal hair shaft production. Engrailed,
a type of homeobox gene is responsible for dorsal-ventral patterning
and mice lacking engrailed develop hair follicles on their footpads.
Mediation of hair follicle melanocyte infiltration
Transgenic and mutant mice have been used to study the genetic
control of the development of melanocytes, and their progenitors,
neural crest cells and melanoblasts. This had led to the identification
of several factors that are important in melanoblast development.
These include SOXlO, the transcription factor PAX3, the basic
helix-loop-helix leucine zipper microphthalmia-associated transcription
factor (MITF), endothelin receptor B, its ligand endothelin 3,
and the receptor tyrosine kinase, KIT, and its ligand mast cell
growth factor (MGF). Experiments in mice show that KIT and MGF
are necessary for the survival, proliferation, and initial migration
of melanoblasts from the neural crest. In addition, they are necessary
in the later movement of melanocytes from the dermis to the epidermis.
The failure of melanocytes to migrate to these locations explains
the association of congenital piebaldism (congenital de- pigmented
patches of the skin) and poliosis (congenital white hair) with
mutations in the KIT gene. Similarly, Waardenburg syndrome (congenital
disease characterized by deafness in association with pigmentary
anomalies and defects of neural crest-derived tissues) can be
caused by mutations in PAX3, MITF, endothelin-B receptor, endothelin-3
or SOXlO.
Molecular
mediators of hair follicle embryogenesis references
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