Patched 1 and Patched 2 Redundancy Has a Key Role in Regulating Epidermal Differentiation
Patched 1 and Patched 2 Redundancy Has a Key Role in Regulating Epidermal Differentiation
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DOI：
10.1038/jid.2014.63
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发表时间：
2014-07-01
影响因子：
6.5
通讯作者：
Wainwright, Brandon J.
中科院分区：
文献类型：
--
作者：
Adolphe, Christelle;Nieuwenhuis, Erica;Wainwright, Brandon J.
Patched 1（Ptch 1）受体在抑制Hedgehog（Hh）通路的活性方面具有关键作用，因此在预防许多人类发育障碍和肿瘤形成方面至关重要。然而，哺乳动物Ptch 2蛋白的功能作用仍然难以捉摸，特别是它在多大程度上有助于调节Hh信号传导的空间和时间活性。在这里，我们证明了在三个独立的小鼠模型的表皮发育，在体内消融的Ptch受体的结果在一个更严重的表型比损失的Ptch 1单独。我们的研究表明，Ptch 1和Ptch 2活性的同时丧失抑制了表皮谱系的特化和分化。这些结果表明，通过动态Ptch调控网络抑制Hh信号传导是皮肤中谱系命运决定的关键事件。总的来说，我们的研究结果暗示Ptch受体冗余是阐明Hh诱导的肿瘤细胞起源的关键问题。
The Patched 1 (Ptch1) receptor has a pivotal role in inhibiting the activity of the Hedgehog (Hh) pathway and is therefore critical in preventing the onset of many human developmental disorders and tumor formation. However, the functional role of the mammalian Ptch2 paralogue remains elusive, particularly the extent to which it contributes to regulating the spatial and temporal activity of Hh signaling. Here we demonstrate in three independent mouse models of epidermal development that in vivo ablation of both Ptch receptors results in a more severe phenotype than loss of Ptch1 alone. Our studies indicate that concomitant loss of Ptch1 and Ptch2 activity inhibits epidermal lineage specification and differentiation. These results reveal that repression of Hh signaling through a dynamic Ptch regulatory network is a crucial event in lineage fate determination in the skin. In general, our findings implicate Ptch receptor redundancy as a key issue in elucidating the cellular origin of Hh-induced tumors.