Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
Dev Biol. 2015 Jan 15;397(2):191-202. doi: 10.1016/j.ydbio.2014.10.023. Epub 2014 Nov 13.
Ptch1 and Ptch2 are highly conserved vertebrate homologs of Drosophila ptc, the receptor of the Hedgehog (Hh) signaling pathway. The vertebrate Ptch1 gene encodes a potent tumor suppressor and is well established for its role in embryonic development. In contrast, Ptch2 is poorly characterized and dispensable for embryogenesis. In flies and mice, ptc/Ptch1 controls Hh signaling through the regulation of Smoothened (Smo). In addition, Hh pathway activation also up-regulates ptc/Ptch1 expression to restrict the diffusion of the ligand. Recent studies have implicated Ptch2 in this ligand dependent antagonism, however whether Ptch2 encodes a functional Shh receptor remains unclear. In this report, we demonstrate that Ptch2 is a functional Shh receptor, which regulates Smo localization and activity in vitro. We also show that Ptch1 and Ptch2 are co-expressed in the developing mouse limb bud and loss of Ptch2 exacerbates the outgrowth defect in the limb-specific Ptch1 knockout mutants, demonstrating that Ptch1 and Ptch2 co-operate in regulating cellular responses to Shh in vivo.
Ptch1 和 Ptch2 是高度保守的脊椎动物果蝇 ptc 的同源物，是 Hedgehog（Hh）信号通路的受体。脊椎动物 Ptch1 基因编码一种有效的肿瘤抑制因子，其在胚胎发育中的作用已得到充分证实。相比之下，Ptch2 的特征描述较差，并且在胚胎发生中可有可无。在果蝇和小鼠中，ptc/Ptch1 通过调节 Smoothened（Smo）来控制 Hh 信号。此外，Hh 通路的激活还上调了 ptc/Ptch1 的表达，以限制配体的扩散。最近的研究表明 Ptch2 参与了这种配体依赖性拮抗作用，但 Ptch2 是否编码功能性 Shh 受体仍不清楚。在本报告中，我们证明了 Ptch2 是功能性的 Shh 受体，它在体外调节 Smo 的定位和活性。我们还表明，Ptch1 和 Ptch2 在发育中的小鼠肢芽中共同表达，并且 Ptch2 的缺失加剧了肢特异性 Ptch1 敲除突变体的生长缺陷，表明 Ptch1 和 Ptch2 共同合作调节体内细胞对 Shh 的反应。
