ANKS6 is a ciliary protein that localizes to the proximal compartment of the primary cilium, where it regulates signaling. Mutations in the ANKS6 gene cause multiorgan ciliopathies in humans, which include laterality defects of the visceral organs, renal cysts as part of nephronophthisis and congenital hepatic fibrosis (CHF) in the liver. Although CHF together with liver ductal plate malformations (DPM) are common features of several human ciliopathy syndromes, including nephronophthisis-related ciliopathies, the mechanism by which mutations in ciliary genes lead to bile duct developmental abnormalities is not understood. Here, we generated a knockout mouse model of Anks6, and show that ANKS6 function is required for bile duct morphogenesis and cholangiocyte differentiation. Loss of Anks6 causes ciliary abnormalities, ductal plate remodeling defects and periportal fibrosis in the liver. Our expression studies and biochemical analyses show that biliary abnormalities in Anks6-deficient livers result from the dysregulation of YAP transcriptional activity in the bile duct-lining epithelial cells. Mechanistically, our studies suggest, that ANKS6 antagonizes Hippo signaling in the liver during bile duct development by binding to Hippo pathway effector proteins YAP1, TAZ and TEAD4 and promoting their transcriptional activity. Together, this study reveals a novel function for ANKS6 in regulating Hippo signaling during organogenesis and provides mechanistic insights to the regulatory network controlling bile duct differentiation and morphogenesis during liver development.

中文翻译：

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Anks6 缺失会导致 YAP 缺陷和肝脏异常。

ANKS6 是一种纤毛蛋白，定位于初级纤毛的近端隔室，在那里它调节信号传导。ANKS6基因突变导致人类多器官纤毛病，包括内脏器官偏侧缺陷、肾囊肿（肾囊肿的一部分）和肝脏先天性肝纤维化 (CHF)。尽管 CHF 和肝导管板畸形 (DPM) 是几种人类纤毛病综合征的共同特征，包括与肾结核相关的纤毛病，但纤毛基因突变导致胆管发育异常的机制尚不清楚。在这里，我们生成了Anks6的敲除小鼠模型，并表明 ANKS6 功能是胆管形态发生和胆管细胞分化所必需的。丢失Anks6导致肝脏纤毛异常、导管板重塑缺陷和门静脉周围纤维化。我们的表达研究和生化分析表明， Anks6缺陷肝脏中的胆道异常是由胆管内壁上皮细胞中 YAP 转录活性失调引起的。我们的研究表明，从机制上讲，ANKS6 通过与 Hippo 通路效应蛋白 YAP1、TAZ 和 TEAD4 结合并促进其转录活性，从而在胆管发育过程中拮抗肝脏中的 Hippo 信号传导。总之，这项研究揭示了 ANKS6 在器官发生过程中调节 Hippo 信号传导的新功能，并为肝脏发育过程中控制胆管分化和形态发生的调节网络提供了机制见解。