The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner
The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner
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DOI：
10.1242/dev.154054
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发表时间：
2018-01-01
期刊：
影响因子：
4.6
通讯作者：
Mukhopadhyay, Saikat
中科院分区：
文献类型：
--
作者：
Hwang, Sun-hee;White, Kevin A.;Mukhopadhyay, Saikat
在肢体/骨骼形态发生过程中，sonic hedgehog Shh通路的基础抑制及其与印度hedgehog Ihh信号的相互作用尚不清楚。孤儿G蛋白偶联受体Gpr161定位于初级纤毛，并通过促进Gli转录抑制因子与激活因子的形成，作为Shh信号的负调节因子。在这里，我们发现Gpr161基因敲除小鼠胚胎中，尽管建立了预期的肢体场，但前肢芽并未形成。肢体特异性缺失Gpr161导致Shh信号过早扩增和异位Shh依赖的模式缺陷，导致多指畸形。此外，前臂软骨内骨形成，包括小梁骨和骨领的形成均被阻止。软骨内骨形成缺陷是由于增生的圆形/关节周围样软骨细胞的积累，缺乏向柱状软骨细胞的分化，以及相应的Ihh信号缺失。颅面间质Gpr161的缺乏也阻碍了颅骨膜内骨的形成。在没有纤毛的情况下，肢体形态、软骨内和膜内骨骼形态发生的缺陷受到抑制。总的来说，Gpr161促进前肢形成，调节肢体模式，阻止关节周围软骨细胞增殖，并以纤毛依赖的方式驱动膜内骨的成骨细胞发生。
The role of basal suppression of the sonic hedgehog Shh) pathway and its interaction with Indian hedgehog Ihh) signaling during limb/skeletal morphogenesis is not well understood. The orphan G protein-coupled receptor Gpr161 localizes to primary cilia and functions as a negative regulator of Shh signaling by promoting Gli transcriptional repressor versus activator formation. Here, we show that forelimb buds are not formed in Gpr161 knockout mouse embryos despite establishment of prospective limb fields. Limb-specific deletion of Gpr161 resulted in prematurely expanded Shh signaling and ectopic Shh-dependent patterning defects resulting in polysyndactyly. In addition, endochondral bone formation in forearms, including formation of both trabecular bone and bone collar was prevented. Endochondral bone formation defects resulted from accumulation of proliferating round/periarticular-like chondrocytes, lack of differentiation into columnar chondrocytes, and corresponding absence of Ihh signaling. Gpr161 deficiency in craniofacial mesenchyme also prevented intramembranous bone formation in calvarium. Defects in limb patterning, endochondral and intramembranous skeletal morphogenesis were suppressed in the absence of cilia. Overall, Gpr161 promotes forelimb formation, regulates limb patterning, prevents periarticular chondrocyte proliferation and drives osteoblastogenesis in intramembranous bones in a cilium-dependent manner.