Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop
Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop
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DOI：
10.1101/gad.187401.112
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发表时间：
2012-06-01
影响因子：
10.5
通讯作者：
Oro, Anthony E.
中科院分区：
文献类型：
--
作者：
Woo, Wei-Meng;Zhen, Hanson H.;Oro, Anthony E.
在毛囊形态发生过程中，真皮乳头（DPs）作为间充质信号中心与上覆上皮细胞相互作用，调节形态发生。虽然DP调节毛囊的形成，但对DP形成的分子基础知之甚少。形态发生素Sonic hedgehog（Shh）以调节毛囊上皮生长而闻名，过度的信号传导导致基底细胞癌。在这里，我们研究了皮肤特异性Shh信号如何有助于DP形成和毛发生长。使用Crelox遗传模型和RNAi在毛囊重建测定中，我们证明了真皮平滑（Smo）功能丧失导致DP前体、真皮冷凝物和第2阶段毛囊停滞表型的丧失，这让人想起Shh（-/-）皮肤。令人惊讶的是，真皮Smo不调节细胞存活或上皮增殖。相反，分子筛选和免疫染色研究表明，真皮Shh信号控制DP特异性标签基因的一个子集的表达。使用发夹/cDNA慢病毒系统，我们表明，Shh依赖的基因头蛋白的过表达，但不是Sox 2或Sox 18，可以部分拯救真皮Smo敲低毛囊表型通过增加上皮Shh的表达。我们的研究结果表明，真皮Shh信号调节特定的DP签名，以维持DP成熟，同时保持一个互惠的Shh-Noggin信号循环，以驱动毛囊形态发生。
During hair follicle morphogenesis, dermal papillae (DPs) function as mesenchymal signaling centers that cross-talk with overlying epithelium to regulate morphogenesis. While the DP regulates hair follicle formation, relatively little is known about the molecular basis of DP formation. The morphogen Sonic hedgehog (Shh) is known for regulating hair follicle epithelial growth, with excessive signaling resulting in basal cell carcinomas. Here, we investigate how dermal-specific Shh signaling contributes to DP formation and hair growth. Using a Crelox genetic model and RNAi in hair follicle reconstitution assays, we demonstrate that dermal Smoothened (Smo) loss of function results in the loss of the DP precursor, the dermal condensate, and a stage 2 hair follicle arrest phenotype reminiscent of Shh(-/-) skin. Surprisingly, dermal Smo does not regulate cell survival or epithelial proliferation. Rather, molecular screening and immunostaining studies reveal that dermal Shh signaling controls the expression of a subset of DP-specific signature genes. Using a hairpin/cDNA lentiviral system, we show that overexpression of the Shh-dependent gene Noggin, but not Sox2 or Sox18, can partially rescue the dermal Smo knockdown hair follicle phenotype by increasing the expression of epithelial Shh. Our findings suggest that dermal Shh signaling regulates specific DP signatures to maintain DP maturation while maintaining a reciprocal Shh-Noggin signaling loop to drive hair follicle morphogenesis.