The mechanisms underlying subcellular targeting of cAMP-generating adenylyl cyclases and processes regulated by their compartmentalization are poorly understood. Here, we identify Ankmy2 as a repressor of the Hedgehog pathway via adenylyl cyclase targeting. Ankmy2 binds to multiple adenylyl cyclases, determining their maturation and trafficking to primary cilia. Mice lacking Ankmy2 are mid-embryonic lethal. Knockout embryos have increased Hedgehog signaling and completely open neural tubes showing co-expansion of all ventral neuroprogenitor markers, comparable to the loss of the Hedgehog receptor Patched1. Ventralization in Ankmy2 knockout is completely independent of the Hedgehog pathway transducer Smoothened. Instead, ventralization results from the reduced formation of Gli2 and Gli3 repressors and early depletion of adenylyl cyclase III in neuroepithelial cilia, implicating deficient pathway repression. Ventralization in Ankmy2 knockout requires both cilia and Gli2 activation. These findings indicate that cilia-dependent adenylyl cyclase signaling represses the Hedgehog pathway and promotes morphogenetic patterning.

对产生 cAMP 的腺苷酸环化酶的亚细胞靶向机制以及受其区室化调节的过程知之甚少。在这里，我们通过腺苷酸环化酶靶向将 Ankmy2 鉴定为 Hedgehog 途径的阻遏物。Ankmy2 与多个腺苷酸环化酶结合，决定它们的成熟和向初级纤毛的运输。缺乏 Ankmy2 的小鼠是胚胎中期致死的。敲除胚胎增加了 Hedgehog 信号传导和完全开放的神经管，显示所有腹侧神经祖细胞标志物的共同扩张，与 Hedgehog 受体Patched1的损失相当。Ankmy2 中的腹化敲除完全独立于 Hedgehog 通路传感器 Smoothened。相反，腹侧化是由于神经上皮纤毛中 Gli2 和 Gli3 阻遏物的形成减少以及腺苷酸环化酶 III 的早期耗竭，暗示通路抑制不足。Ankmy2 敲除中的Ventralization需要纤毛和 Gli2 激活。这些发现表明纤毛依赖性腺苷酸环化酶信号抑制 Hedgehog 通路并促进形态发生模式。