Chen Alice E, Ginty David D, Fan Chen-Ming
Department of Embryology, Carnegie Institution of Washington, 115 West University Parkway, Baltimore, Maryland 21210, USA.
Nature. 2005 Jan 20;433(7023):317-22. doi: 10.1038/nature03126. Epub 2004 Nov 28.
Select members of the Wnt family of secreted glycoproteins have been implicated in inducing the myogenic determinant genes Pax3, MyoD and Myf5 during mammalian embryogenesis, but the mechanism of induction has not been defined. We describe an unexpected role for protein kinase A (PKA) signalling via CREB in this induction. Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for Wnt-directed myogenic gene expression. Wnt proteins can also stimulate CREB-mediated transcription, providing evidence for a Wnt signalling pathway involving PKA and CREB. Our findings raise the possibility that PKA/CREB signalling may also contribute to other Wnt-regulated processes in embryonic patterning, stem cell renewal and cancer.
分泌型糖蛋白Wnt家族的某些成员在哺乳动物胚胎发育过程中参与诱导生肌决定基因Pax3、MyoD和Myf5，但诱导机制尚未明确。我们描述了蛋白激酶A（PKA）通过CREB信号传导在这种诱导过程中发挥的意想不到的作用。通过体外外植体试验、突变分析以及将基因导入体外培养的小鼠胚胎相结合的方法，我们证明由PKA介导的腺苷酸环化酶信号传导及其靶转录因子CREB是Wnt定向生肌基因表达所必需的。Wnt蛋白还能刺激CREB介导的转录，为涉及PKA和CREB的Wnt信号通路提供了证据。我们的研究结果提出了一种可能性，即PKA/CREB信号传导也可能在胚胎模式形成、干细胞更新和癌症等其他Wnt调节过程中发挥作用。
