Background: Despite different pathogenic mechanisms, two of the most common hair growth disorder (androgenic alopecia and alopecia areata) are characterized by hair follicle miniaturization with significant elongation of the resting stage, shortening of the growth stage of the hair cycle, and hair loss. Molecular signals that trigger hair follicle induction in embroyonic skin, as well as cyclic transformation from resting to active growth and from active growth to regression during postnatal development, in normal skin and in skin affected by hair growth disorders, are still poorly understood. Bone morphogenic proteins 2/4 (BMP2/4), members of transforming growth factor- beta/BMP superfamily, and their specific antagonist noggin, which binds BMP2/4 with high affinity and prevents their interactions with BMP receptors, play essential roles in the control of induction of ectodermal derivatives (neural tube, tooth, feather) and in the regulation of apoptotic cell death during development. While BMP2/4 inhibit morphogenesis and reduct the size of developing organs, the BMP- antagonist noggin stimulates morphogenesis and downregulates BMP- mediated apoptosis. Hypothesis: neutralization of BMP2/4 signaling by their antagonist noggin plays important roles: i) in the control of hair follicle induction during embryogenesis, ii) in the initiation of new hair growth phase in postnatal skin, iii) in the regulation of apoptosis-driven hair follicle regression in normal skin affected by most common hair growth disorders. Purpose: 1) Study hair follicle development in the embryonic skin of noggin knockout mice transplanted into SCID mice. 2) Characterize expression of noggin, BMP2/4, BMP-receptors during hair follicle cycling in normal postnatal C57BL/6 mouse and human skin, in the alopecia areata-affected C3H/HeJ mice, and in human skin affected by hair growth disorders. 3) Define effects of noggin/BMP2/4 on hair cycle in mouse and human skin in vivo and in situ. 4) Determine in vivo function of noggin in skin by generation of noggin-overexpressing mice under control of K14 and versican promoters. Significance: Investigation of the in vivo functions of noggin and BMP2/4 as putative modulators of hair follicle induction and cycling in normal skin and in skin affected by hair growth disorders (androgenic alopecia, alopecia areata) will provide important new knowledge into hair cycle biology and will rise a possibility to explore to explore BMP- antagonists for the treatment of these disorders.
|Botchkarev, Vladimir A; Sharov, Andreij A (2004) BMP signaling in the control of skin development and hair follicle growth. Differentiation 72:512-26|
|Sharov, Andrei A; Weiner, Lorin; Sharova, Tatyana Y et al. (2003) Noggin overexpression inhibits eyelid opening by altering epidermal apoptosis and differentiation. EMBO J 22:2992-3003|
|Botchkarev, Vladimir A; Botchkareva, Natalia V; Sharov, Andrei A et al. (2002) Modulation of BMP signaling by noggin is required for induction of the secondary (nontylotrich) hair follicles. J Invest Dermatol 118:3-10|
|Botchkarev, V A; Botchkareva, N V; Nakamura, M et al. (2001) Noggin is required for induction of the hair follicle growth phase in postnatal skin. FASEB J 15:2205-14|