Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway.
Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway.
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协调的D-Cyclin/FOXD1激活驱动声波刺猬信号通路的有丝分裂活性。
DOI：
10.1016/j.cellsig.2017.12.007
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发表时间：
2018-04
影响因子：
4.8
通讯作者：
Lipinski RJ
中科院分区：
文献类型：
--
作者：
Fink DM;Sun MR;Heyne GW;Everson JL;Chung HM;Park S;Sheets MD;Lipinski RJ
Sonic Hedgehog（Shh）信号在胚胎发育和出生后的稳态和修复中起着关键的调节作用。已知Shh通路的调节引起与失调的组织生长相关的畸形和恶性肿瘤。然而，我们对Shh调节细胞增殖的分子机制的理解是不完整的。在这里，使用小鼠胚胎成纤维细胞，我们证明了叉头盒基因Foxd 1的转录调控的经典Shh信号和下游增殖活性所需的。我们发现，FOXD 1缺失废除了SHH配体的增殖反应，而FOXD 1过表达单独足以诱导细胞增殖。对SHH配体和FOXD 1过表达的增殖反应通过对细胞周期蛋白依赖性激酶信号传导的药理学抑制来阻断。时程实验表明，Shh途径激活Foxd 1后下调Cdkn 1c，它编码一个细胞周期蛋白依赖性激酶抑制剂。与直接的转录调控机制相一致，我们发现FOXD 1降低了Cdkn 1c第二内含子中Fox增强子序列的报告活性。支持这些研究结果的适用性，以特定的生物背景下，我们表明，Shh的调节Foxd 1和Cdkn 1c是概括在颅神经嵴细胞，并提供证据表明，这种机制是在上唇形态发生的操作。这些结果揭示了一种新的Shh-Foxd 1-Cdkn 1c调节电路，该电路驱动Shh信号的促有丝分裂作用，并可能在发育和疾病中具有广泛的意义。
Sonic Hedgehog (Shh) signaling plays key regulatory roles in embryonic development and postnatal homeostasis and repair. Modulation of the Shh pathway is known to cause malformations and malignancies associated with dysregulated tissue growth. However, our understanding of the molecular mechanisms by which Shh regulates cellular proliferation is incomplete. Here, using mouse embryonic fibroblasts, we demonstrate that the Forkhead box gene Foxd1 is transcriptionally regulated by canonical Shh signaling and required for downstream proliferative activity. We show that Foxd1 deletion abrogates the proliferative response to SHH ligand while FOXD1 overexpression alone is sufficient to induce cellular proliferation. The proliferative response to both SHH ligand and FOXD1 overexpression was blocked by pharmacologic inhibition of cyclin-dependent kinase signaling. Time-course experiments revealed that Shh pathway activation of Foxd1 is followed by downregulation of Cdkn1c, which encodes a cyclin-dependent kinase inhibitor. Consistent with a direct transcriptional regulation mechanism, we found that FOXD1 reduces reporter activity of a Fox enhancer sequence in the second intron of Cdkn1c. Supporting the applicability of these findings to specific biological contexts, we show that Shh regulation of Foxd1 and Cdkn1c is recapitulated in cranial neural crest cells and provide evidence that this mechanism is operational during upper lip morphogenesis. These results reveal a novel Shh-Foxd1-Cdkn1c regulatory circuit that drives the mitogenic action of Shh signaling and may have broad implications in development and disease.
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