Biomedical Engineering Reference
In-Depth Information
morphogenesis whereas repression of signalling results in differentiation in
sebocytes and interfollicular epidermis (Niemann and Watt, 2002). Different
regions of the epidermis differ in their sensitivity to a given level of beta-
catenin activation (Lowry et al., 2005). Furthermore, sustained activation of
low levels of b-catenin results in mobilization of stem cells in the bulge (Lowry
et al., 2005). Stem cell activation by low-level Wnt/beta-catenin signalling was
reflected by precocious entry into anagen, the phase of new hair follicle growth.
Shifting the activation state of the stem cell compartment occurred without gross
perturbations of the stem cell niche as size and morphology and expression of
stem cell markers of the bulge region remain unaffected. On the other hand, the
gene ablation of b-catenin in the skin results in failure of the stem cell niche to
express their characteristic marker molecules (Lowry, 2005; Huelsken et al.,
2001). Two pathways intersect the Wnt pathway in epidermis, the Notch and
vitamin D pathways. Notch 1 is an essential factor of postnatal hair follicle
development and homeostasis (Vauclair et al., 2005). On the other hand, loss of
mutation on vitamin D receptor is associated with hair loss in mice and humans
(Shah et al., 2006).
In stem cell progeny, Wnt/beta-catenin signalling activates a set of genes
associated with the proliferation of hair follicle keratinocytes such as Sonic
Hedgehog (Shh), Patched (Ptc), bone morphogenic proteins (BMP 2/4), FoxN1
(Gat et al., 1998; Silva-Varges et al., 2005;). Pharmacological inhibition of Shh
signalling in combination with moderate activation of beta-catenin, blocks de
novo hair follicle formation (Silva-Vargas et al., 2005). Conversely, inhibition
of Shh signalling improves morphogenesis in response to high levels of beta-
catenin activation (Silva-Varges et al., 2005). Sox9 expression is dependent on
Shh and deletion of Sox9 in the epidermis results in hair loss and failure to form
a bulge (Vidal et al., 2005).
Involvement of Notch signalling in postdevelopmental stem cell system is best
understood in the skin, particularly in the hair follicles. Notch1, Notch2 and
Notch3 are expressed and differentially localized to various layers of the hair
follicle (Powell et al., 1998; Pan et al., 2004). Notch signals do not affect the
pattern of skin formation during embryogenesis. After birth, the first cycle of
Notch-1 null mice shows a shortened anagen phase and premature entry into the
catagen phase, and inactivation of Notch1 in adult mice results in almost complete
hair loss followed by cyst formation. Thereby, Notch1 is essential for postnatal
hair follicle development and homeostasis (Pan et al., 2004; Vauclair et al., 2005).
Notch over-activity in hair follicle cells also leads to abnormal hair forma-
tion (Lin et al., 2000; Uyttenadaele et al., 2004). In summary, Notch signals are
likely to promote the selection of hair formation in bulge stem cells. Recently,
Notch signalling acting through Hes 1 was demonstrated to play a crucial role
in the survival of immature melanoblasts and melanocyte stem cells by prevent-
ing initiation of apoptosis (Moriyama et al., 2006).
Interestingly, p63 a homolog of the p53 tumour suppressor in skin develop-
ment was revealed by two independent studies of p63-deficient mice. These mice
lack stratified epidermis, producing a disorganized single-layered surface
