Open AccessRac1 Signaling Is Required for Anterior Second Heart Field Cellular Organization and Cardiac Outflow Tract Development
Author(s) -
Leung Carmen,
Liu Yin,
Lu Xiangru,
Kim Mella,
Drysdale Thomas A.,
Feng Qingping
Publication year - 2016
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.115.002508
Subject(s) - medicine , microbiology and biotechnology , heart development , embryonic stem cell , mesoderm , anatomy , lateral plate mesoderm , endocrinology , biology , genetics , gene
Background The small GTP ase Rac1 regulates diverse cellular functions, including both apicobasal and planar cell polarity pathways; however, its role in cardiac outflow tract ( OFT ) development remains unknown. In the present study, we aimed to examine the role of Rac1 in the anterior second heart field ( SHF ) splanchnic mesoderm and subsequent OFT development during heart morphogenesis. Methods and Results Using the Cre/loxP system, mice with an anterior SHF ‐specific deletion of Rac1 ( Rac1 SHF ) were generated. Embryos were collected at various developmental time points for immunostaining and histological analysis. Intrauterine echocardiography was also performed to assess aortic valve blood flow in embryos at embryonic day 18.5. The Rac1 SHF splanchnic mesoderm exhibited disruptions in SHF progenitor cellular organization and proliferation. Consequently, this led to a spectrum of OFT defects along with aortic valve defects in Rac1 SHF embryos. Mechanistically, it was found that the ability of the Rac1 SHF OFT myocardial cells to migrate into the proximal OFT cushion was severely reduced. In addition, expression of the neural crest chemoattractant semaphorin 3c was decreased. Lineage tracing showed that anterior SHF contribution to the OFT myocardium and aortic valves was deficient in Rac1 SHF hearts. Furthermore, functional analysis with intrauterine echocardiography at embryonic day 18.5 showed aortic valve regurgitation in Rac1 SHF hearts, which was not seen in control hearts. Conclusions Disruptions of Rac1 signaling in the anterior SHF results in aberrant progenitor cellular organization and defects in OFT development. Our data show Rac1 signaling to be a critical regulator of cardiac OFT formation during embryonic heart development.