Ankmy2 Prevents Smoothened-Independent Hyperactivation of the Hedgehog Pathway via Cilia-Regulated Adenylyl Cyclase Signaling.
Ankmy2 Prevents Smoothened-Independent Hyperactivation of the Hedgehog Pathway via Cilia-Regulated Adenylyl Cyclase Signaling.
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DOI：
10.1016/j.devcel.2020.06.034
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发表时间：
2020-09-28
影响因子：
11.8
通讯作者：
Mukhopadhyay S
中科院分区：
文献类型：
--
作者：
Somatilaka BN;Hwang SH;Palicharla VR;White KA;Badgandi H;Shelton JM;Mukhopadhyay S
产生cAMP的腺苷酸环化酶的亚细胞靶向机制和由其区室化调节的过程知之甚少。在这里，我们确定Ankmy2作为刺猬途径的阻遏物通过腺苷酸环化酶靶向。Ankmy2与多种腺苷酸环化酶结合，决定它们的成熟和运输到初级纤毛。缺乏Ankmy2的小鼠是胚胎中期致死的。敲除胚胎具有增加的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记物的共扩增，与Hedgehog受体Patched1的损失相当。Ankmy 2敲除中的腹侧化完全独立于Hedgehog途径换能器Smoothened。相反，腹侧化的结果从减少形成Gli2和Gli3阻遏物和早期耗尽的腺苷酸环化酶III在神经上皮纤毛，牵连缺陷的途径抑制。Ankmy2敲除中的细胞分化需要纤毛和Gli2激活。这些发现表明，纤毛依赖的腺苷酸环化酶信号抑制刺猬途径，促进形态发生模式。Somatilaka等人将Ankmy2鉴定为Hedgehog途径的阻遏物。Ankmy2敲除小鼠显示完全的神经管腹侧化，独立于Smoothened，但需要纤毛和Gli2。Ankmy 2调节腺苷酸环化酶的成熟和向纤毛的运输，暗示纤毛依赖性腺苷酸环化酶信号传导参与Gli抑制子的形成和形态发生模式。
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. Somatilaka et al. identify Ankmy2 as a repressor of the Hedgehog pathway. Ankmy2 knockout mouse show complete neural tube ventralization independently of Smoothened but requiring cilia and Gli2. Ankmy2 regulates maturation of adenylyl cyclases and trafficking to cilia, implicating cilia-dependent adenylyl cyclase signaling in Gli-repressor formation and morphogenetic patterning.
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