Assuntos
Carcinoma Basocelular/genética , Transformação Celular Neoplásica/genética , Regulação da Expressão Gênica , Neoplasias Primárias Múltiplas/genética , Proteínas/fisiologia , Neoplasias Cutâneas/genética , Transativadores , Fatores de Transcrição/genética , Animais , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Bovinos , Epiderme/metabolismo , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Proteínas Hedgehog , Queratinócitos/metabolismo , Queratinas/genética , Fatores de Transcrição Kruppel-Like , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Primárias Múltiplas/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição/fisiologia , Proteína Gli2 com Dedos de ZincoRESUMO
The hair follicle is a source of epithelial stem cells and site of origin for several types of skin tumors. Although it is clear that follicles arise by way of a series of inductive tissue interactions, identification of the signaling molecules driving this process remains a major challenge in skin biology. In this study we report an obligatory role for the secreted morphogen Sonic hedgehog (Shh) during hair follicle development. Hair germs comprising epidermal placodes and associated dermal condensates were detected in both control and Shh -/- embryos, but progression through subsequent stages of follicle development was blocked in mutant skin. The expression of Gli1 and Ptc1 was reduced in Shh -/- dermal condensates and they failed to evolve into hair follicle papillae, suggesting that the adjacent mesenchyme is a critical target for placode-derived Shh. Despite the profound inhibition of hair follicle morphogenesis, late-stage follicle differentiation markers were detected in Shh -/- skin grafts, as well as cultured vibrissa explants treated with cyclopamine to block Shh signaling. Our findings reveal an essential role for Shh during hair follicle morphogenesis, where it is required for normal advancement beyond the hair germ stage of development.