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Dev Cell. 2016 Sep 12;38(5):478-92. doi: 10.1016/j.devcel.2016.08.002. Epub 2016 Sep 1.

Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.

Author information

1
Program in Vertebrate Developmental Biology, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
2
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.
3
Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
4
Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: patrick.lusk@yale.edu.
5
Program in Vertebrate Developmental Biology, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: mustafa.khokha@yale.edu.

Abstract

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.

KEYWORDS:

3D nanoscopy; Xenopus tropicalis; congenital heart disease; heterotaxy; left-right patterning; nuclear pore complex; nucleoporin; super-resolution

PMID:
27593162
PMCID:
PMC5021619
[Available on 2017-09-12]
DOI:
10.1016/j.devcel.2016.08.002
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