Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development

Abstract

Sonic hedgehog (Shh) signaling plays a critical role in hair follicle development and skin cancer, but how it controls these processes remains unclear. Of the three Gli transcription factors involved in transducing Shh signals in vertebrates, we demonstrate here that Gli2 is the key mediator of Shh responses in skin. Similar to Shh −/− mice, Gli2 −/− mutants exhibit an arrest in hair follicle development with reduced cell proliferation and Shh-responsive gene expression, but grossly normal epidermal differentiation. By transgenic rescue experiments, we show that epidermal Gli2 function alone is sufficient to restore hair follicle development in Gli2 −/− skin. Furthermore, only a constitutively active form of Gli2, but not wild-type Gli2, can activate Shh-responsive gene expression and promote cell proliferation in Shh −/− skin. These observations indicate that Shh-dependent Gli2 activator function in the epidermis is essential for hair follicle development. Our data also reveal that Gli2 mediates the mitogenic effects of Shh by transcriptional activation of cyclin D1 and cyclin D2 in the developing hair follicles. Together, our results suggest that Shh-dependent Gli2 activation plays a critical role in epithelial homeostasis by promoting proliferation through the transcriptional control of cell cycle regulators.[Keywords: Shh; Gli2; hair follicle; mitogen; D-type cyclins] Supplemental material is available at http://www.genesdev.org.

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

“…1a and data not shown). This pattern, consistently observed during consecutive hair cycles (data not shown), parallels that of Shh target proteins, which are expressed in anagen and cease in telogen (16).…”

Transcriptional control of epidermal specification and differentiation

“…Overexpression of Gli2 in the proliferating cells of the epidermis leads to basal cell carcinomas in transgenic mice [19]. Conversely, Gli2 −/− mice phenocopy the Shh −/− mice in their reduced proliferation in the hair follicles [20]. No apparent proliferation defect was noted in the IFE of Gli2 −/− mice, although further in vitro experiments may still reveal a role.…”

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

“…In adult mouse skin SHH is required for the normal hair growth cycle (17), and treatment with antibodies to SHH blocks the growth of anagen hair follicles (18). In both the knockouts and the antibody-treated epidermis some markers of follicular differentiation are expressed, and it seems that SHH is primarily required for growth rather than differentiation (16,19,20).…”

“…Mice that are homozygous null for Indian hedgehog (IHH) have major skeletal defects and die at birth, but no analysis of their skin has been described (15). GLI2 is the key mediator of SHH responses in skin and positively regulates GLI1; GLI2 knockout mice show a similar arrest in hair follicle development to SHH null animals (16). In adult mouse skin SHH is required for the normal hair growth cycle (17), and treatment with antibodies to SHH blocks the growth of anagen hair follicles (18).…”