The Ciliary G-Protein-Coupled Receptor Gpr161 Negatively Regulates the Sonic Hedgehog Pathway via cAMP Signaling
The Ciliary G-Protein-Coupled Receptor Gpr161 Negatively Regulates the Sonic Hedgehog Pathway via cAMP Signaling
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DOI：
10.1016/j.cell.2012.12.026
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发表时间：
2013-01-17
期刊：
影响因子：
64.5
通讯作者：
Jackson, Peter K.
中科院分区：
文献类型：
--
作者：
Mukhopadhyay, Saikat;Wen, Xiaohui;Jackson, Peter K.
在脊椎动物中，初级纤毛是Sonic Hedgehog(Shh)信号所必需的。与影响纤毛组装的突变不同，鞭毛内运输复合体A(IFT-A)的突变相反地导致Shh信号增加。我们以前证明了IFT-A复合体，除了在逆行IFT中的典型作用外，还与管状蛋白Tulp3结合，并将其招募到纤毛。在这里，我们描述了一个保守的脊椎动物G蛋白偶联受体GPR161，它以Tulp3/IFT-A依赖的方式定位于初级纤毛。在小鼠中，GPR161的完全缺失会导致中期妊娠死亡，并增加神经管中的Shh信号，表现为Tulp3/IFT-A突变。GPR161的结构性活性通过决定Gli3对其抑制子形式的处理来增加cAMP水平并抑制Shh信号。相反，Shh信号引导GPR161从纤毛内化，阻止其活动。因此，GPR161定义了一条在神经管发育过程中将蛋白激酶A激活与Shh信号偶联的形态发生途径。
The primary cilium is required for Sonic hedgehog (Shh) signaling in vertebrates. In contrast to mutants affecting ciliary assembly, mutations in the intraflagellar transport complex A (IFT-A) paradoxically cause increased Shh signaling. We previously showed that the IFT-A complex, in addition to its canonical role in retrograde IFT, binds to the tubby-like protein, Tulp3, and recruits it to cilia. Here, we describe a conserved vertebrate G-protein-coupled receptor, Gpr161, which localizes to primary cilia in a Tulp3/IFT-A-dependent manner. Complete loss of Gpr161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants. Constitutive Gpr161 activity increases cAMP levels and represses Shh signaling by determining the processing of Gli3 to its repressor form. Conversely, Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. Thus, Gpr161 defines a morphogenetic pathway coupling protein kinase A activation to Shh signaling during neural tube development.