Conditional Disruption of Hedgehog Signaling Pathway Defines its Critical Role in Hair Development and Regeneration

Abstract

Members of the vertebrate hedgehog family (Sonic, Indian, and Desert) have been shown to be essential for the development of various organ systems, including neural, somite, limb, skeletal, and for male gonad morphogenesis. Sonic hedgehog and its cognate receptor Patched are expressed in the epithelial and/or mesenchymal cell components of the hair follicle. Recent studies have demonstrated an essential role for this pathway in hair development in the skin of Sonic hedgehog null embryos. We have further explored the role of the hedgehog pathway using anti-hedgehog blocking monoclonal antibodies to treat pregnant mice at different stages of gestation and have generated viable offspring that lack body coat hair. Histologic analysis revealed the presence of ectodermal placode and primodium of dermal papilla in these mice, yet the subsequent hair shaft formation was inhibited. In contrast, the vibrissae (whisker) development appears to be unaffected upon anti-hedgehog blocking monoclonal antibody treatment. Strikingly, inhibition of body coat hair morphogenesis also was observed in mice treated postnatally with anti-hedgehog monoclonal antibody during the growing (anagen) phase of the hair cycle. The hairless phenotype was reversible upon suspension of monoclonal antibody treatment. Taken together, our results underscore a direct role of the Sonic hedgehog signaling pathway in embryonic hair follicle development as well as in subsequent hair cycles in young and adult mice. Our system of generating an inducible and reversible hairless phenotype by anti-hedgehog monoclonal antibody treatment will be valuable for studying the regulation and mechanism of hair regeneration.

Hedgehog Signaling Regulates Sebaceous Gland Development

“…53 Hair follicles and sebaceous glands both undergo cyclic changes after birth, 54 and Shh plays a major role in regulating proliferation of follicle epithelium during times of active growth. 17 Thus, in addition to its involvement in the initiation of sebaceous gland formation, the Hedgehog pathway is also likely to play a role in postnatal function of sebaceous glands. Acne is the most common skin disease in humans, and in its most severe forms it can lead to significant disfigurement and emotional distress.…”

“…13,14 Hedgehog signaling plays a complementary role, as it is essential for the proliferative expansion of hair follicle epithelium but is not required during follicle initiation or hair lineage differentiation. [15][16][17] Given the involvement of Hedgehog proteins in regulating cell lineage specification in several other organs, 18 we tested the potential involvement of this pathway in cell fate decisions in skin using both loss-of-function and gain-of-function transgenic mouse models. We find that inhibition of Hedgehog signaling in cutaneous keratinocytes selectively blocks the formation of sebocytes.…”

Identification and characterization of Grainyhead‐like epithelial transactivator (GET‐1), a novel mammalian Grainyhead‐like factor

“…In large part, this regulation is achieved at the level of gene transcription, and in recent years, several signaling pathways and transcription factors important for epithelial morphogenesis have been described. These include pathways involving Wnt ligands, ␤-catenin and Lef/Tcf transcription factors (Zhou et al, 1995;Kratochwil et al, 1996;Gat et al, 1998;DasGupta and Fuchs, 1999;Huelsken et al, 2001;Merrill et al, 2001), as well as Shh ligands, and patched and Gli transcription factors (Bitgood and McMahon, 1995;Oro et al, 1997;StJacques et al, 1998;Chiang et al, 1999;Wang et al, 2000). Of interest, the developmental roles of these pathways are conserved from Drosophila to mammals, suggesting the possibility that the function of other regulators involved in developmental control of epidermis in Drosophila may be conserved in mammals (Oro and Scott, 1998;Fuchs et al, 2001).…”

Sonic Hedgehog Regulates Integrin Activity, Cadherin Contacts, and Cell Polarity to Orchestrate Neural Tube Morphogenesis

“…Two blocking antibodies against SHH protein, mAbs 5E1 and APG6, were also used to antagonize SHH activity (Wang et al, 2000). Injection of 5E1 (Fig.…”