Journal
DEVELOPMENTAL CELL
Volume 38, Issue 5, Pages 478-492Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2016.08.002
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Funding
- Brown-Coxe Postdoctoral Fellowship
- NIH [R01 HL124402, P30 DK45735, T32GM007223]
- Wellcome Trust [095927/A/11/Z]
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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.
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