WDR1-regulated actin dynamics is required for outflow tract and right ventricle development

Jisheng Hu; Yingchao Shi; Meng Xia; Zhongying Liu; Ruirui Zhang; Hongmei Luo; Tongcun Zhang; Zhongzhou Yang; Baiyin Yuan

doi:10.1016/j.ydbio.2018.04.004

WDR1-regulated actin dynamics is required for outflow tract and right ventricle development

Dev Biol. 2018 Jun 15;438(2):124-137. doi: 10.1016/j.ydbio.2018.04.004. Epub 2018 Apr 11.

Authors

Jisheng Hu¹, Yingchao Shi², Meng Xia², Zhongying Liu¹, Ruirui Zhang¹, Hongmei Luo², Tongcun Zhang¹, Zhongzhou Yang³, Baiyin Yuan⁴

Affiliations

¹ Biomedical Research Institute, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei Province 430065, China.
² MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
³ MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China. Electronic address: zhongzhouyang@nju.edu.cn.
⁴ Biomedical Research Institute, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei Province 430065, China. Electronic address: yuanby@wust.edu.cn.

PMID: 29654745
DOI: 10.1016/j.ydbio.2018.04.004

Abstract

Outflow tract (OFT) anomalies account for about 30% of human congenital heart defects detected at birth. The second heart field (SHF) progenitors contribute to OFT and right ventricle (RV) development, but the process largely remains unknown. WDR1 (WD-repeat domain 1) is a major co-factor of actin depolymerizing factor (ADF)/cofilin that actively disassembles ADF/cofilin-bound actin filaments. Its function in embryonic heart development has been unknown. Using Wdr1 floxed mice and Nkx2.5-Cre, we deleted Wdr1 in embryonic heart (Wdr1^F/F;Nkx2.5-Cre) and found that these mice exhibited embryonic lethality, and hypoplasia of OFT and RV. To investigate the role of WDR1 in OFT and RV development, we generated SHF progenitors-specific Wdr1 deletion mice (shfKO). shfKO mice began to die at embryonic day 11.5 (E11.5), and displayed decreased size of the proximal OFT and RV at E10.5. In shfKO embryos, neither the number of SHF cells deployment to OFT nor cell proliferation and the cell number were changed, whereas the cellular organization and myofibrillar assembly of cardiomyocytes were severely disrupted. In the proximal OFT and RV of both shfKO and Wdr1^F/F;Nkx2.5-Cre embryos, cardiomyocytes were dissociated from the outer compact myocardial layer and loosely and disorderly arranged into multilayered myocardium. Our results demonstrate that WDR1 is indispensable for normal OFT and RV development, and suggest that WDR1-mediated actin dynamics functions in controlling the size of OFT and RV, which might through regulating the spatial arrangement of cardiomyocytes.

Keywords: Actin; Mouse; Second heart field; WDR1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / metabolism
Animals
Embryo, Mammalian / embryology
Embryonic Development / genetics
Embryonic Development / physiology
Gene Expression Regulation, Developmental / genetics
Heart / embryology
Heart Defects, Congenital / genetics
Heart Ventricles / embryology*
Mice
Mice, Knockout
Microfilament Proteins / genetics
Microfilament Proteins / metabolism
Microfilament Proteins / physiology*
Myocardium
Myocytes, Cardiac
Organogenesis
Signal Transduction
Ventricular Outflow Obstruction

Substances

Actins
Microfilament Proteins
Wdr1 protein, mouse