PDF(Pubmed)
Abstract：
Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness. Mechanisms by which ciliary robustness is ensured in SHH-stimulated cells are not yet known. Herein, we reveal a crosstalk circuit induced by SHH activation of Phospholipase A2α that drives ciliary E-type prostanoid receptor 4 (EP4) signaling to ensure PC function and stabilize ciliary length. We demonstrate that blockade of SHH-EP4 crosstalk destabilizes PC cyclic AMP (cAMP) equilibrium, slows ciliary transport, reduces ciliary length, and attenuates SHH pathway induction. Accordingly, Ep4-/- mice display shortened neuroepithelial PC and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates coordination between distinct ciliary receptors to maintain PC function and length homeostasis for robust downstream signaling.
摘要：
SonicHedgehog（SHH）是胚胎模式的驱动力，当损坏时，引发发育障碍和癌症。SHH效应反应是通过初级纤毛（PC）组织的，该纤毛随着细胞周期的生长和缩回并响应细胞外提示。PC稳态的破坏会破坏SHH调节，对维持纤毛健康的途径施加显著压力。在SHH刺激的细胞中确保纤毛鲁棒性的机制尚不清楚。在这里，我们揭示了由SHH激活磷脂酶A2α引起的串扰电路，该电路驱动纤毛E型前列腺素受体4（EP4）信号传导以确保PC功能并稳定纤毛长度。我们证明了SHH-EP4串扰的阻断会使PC循环AMP（cAMP）平衡不稳定，减慢纤毛运输，减少纤毛长度，并减弱SHH途径的诱导。因此，Ep4-/-小鼠表现出缩短的神经上皮PC和改变的SHH依赖性神经元细胞命运规范。因此，SHH启动不同纤毛受体之间的协调，以维持PC功能和长度稳态，以实现强大的下游信号传导。
