Del Viso Florencia, Huang Fang, Myers Jordan, Chalfant Madeleine, Zhang Yongdeng, Reza Nooreen, Bewersdorf Joerg, Lusk C Patrick, Khokha Mustafa K
Program in Vertebrate Developmental Biology, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Weldon School of Biomedical Engineering, College of Engineering, Purdue University, West Lafayette, IN 47907, USA.
Dev Cell. 2016 Sep 12;38(5):478-92. doi: 10.1016/j.devcel.2016.08.002. Epub 2016 Sep 1.
Human genomics is identifying candidate genes for congenital heart disease (CHD), but discovering the underlying mechanisms remains challenging. In a patient with CHD and heterotaxy (Htx), a disorder of left-right patterning, we previously identified a duplication in Nup188. However, a mechanism to explain how a component of the nuclear pore complex (NPC) could cause Htx/CHD was undefined. Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact. Many data, including the localization of endogenous Nup188/93 at cilia bases, support their direct role at cilia. Super-resolution imaging of Nup188 shows two barrel-like structures with dimensions and organization incompatible with an NPC-like ring, arguing against a proposed "ciliary pore complex." We suggest that the nanoscale organization and function of nucleoporins are context dependent in a way that is required for the structure of the heart.
人类基因组学正在确定先天性心脏病（CHD）的候选基因，但发现其潜在机制仍然具有挑战性。在一名患有先天性心脏病和内脏反位（Htx，一种左右模式紊乱）的患者中，我们之前发现了Nup188基因的重复。然而，尚不清楚核孔复合体（NPC）的一个组成部分如何导致内脏反位/先天性心脏病的机制。在这里，我们表明，敲低Nup188或其结合伴侣Nup93会导致胚胎发育过程中纤毛丢失，而NPC功能基本保持完整。包括内源性Nup188/93在纤毛基部的定位在内的许多数据，都支持它们在纤毛处的直接作用。Nup188的超分辨率成像显示出两个桶状结构，其尺寸和组织与类似NPC的环不兼容，这与所提出的“纤毛孔复合体”相矛盾。我们认为，核孔蛋白的纳米级组织和功能在某种程度上取决于心脏结构所需的环境。
