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XB-ART-55418
Development January 1, 2018; 145 (23):

WDR5 regulates left-right patterning via chromatin-dependent and -independent functions.



Abstract
Congenital heart disease (CHD) is a major cause of infant mortality and morbidity, yet the genetic causes and mechanisms remain opaque. In a patient with CHD and heterotaxy, a disorder of left-right (LR) patterning, a de novo mutation was identified in the chromatin modifier gene WDR5 WDR5 acts as a scaffolding protein in the H3K4 methyltransferase complex, but a role in LR patterning is unknown. Here, we show that Wdr5 depletion leads to LR patterning defects in Xenopus via its role in ciliogenesis. Unexpectedly, we find a dual role for WDR5 in LR patterning. First, WDR5 is expressed in the nuclei of monociliated cells of the LR organizer (LRO) and regulates foxj1 expression. LR defects in wdr5 morphants can be partially rescued with the addition of foxj1 Second, WDR5 localizes to the bases of cilia. Using a mutant form of WDR5, we demonstrate that WDR5 also has an H3K4-independent role in LR patterning. Guided by the patient phenotype, we identify multiple roles for WDR5 in LR patterning, providing plausible mechanisms for its role in ciliopathies like heterotaxy and CHD.

PubMed ID: 30377171
PMC ID: PMC6288385
Article link: Development
Grant support: [+]
Genes referenced: arl13b dand5 dkk1 dnah9 foxj1 foxj1.2 lefty myf5 nodal1 nodal3.1 otx2 pitx2 rfx2 shh sox2 tuba4b tubg1 wdr5 wnt8a
GO keywords: heart development [+]
Antibodies: Arl13b Ab3 Tuba4b Ab5 Tubg1 Ab4 wdr5 Ab1
Morpholinos: wdr5 MO4 wdr5 MO5

Disease Ontology terms: visceral heterotaxy [+]
OMIMs: HETEROTAXY, VISCERAL, 1, X-LINKED; HTX1

Article Images: [+] show captions


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