Lack of Gata3 results in conotruncal heart anomalies in mouse

Abstract

The transcription factor Gata3 is an important regulator of the development of thymus, the nervous system, ear, kidney, and adrenal glands. This study analyzes the role of Gata3 in the developing heart using a mouse strain containing an nlsLacZ reporter gene fused in frame to the Gata3 gene by homologous recombination. Using in situ hybridization, RT-PCR and Gata3-LacZ histochemistry, Gata3 expression was shown in various cardiac structures up to newborn stage. During looping stages (E9.5-E11.5) Gata3-LacZ activity recapitulated endogenous Gata3 and was abundantly expressed in the endocardial ridges and endothelium of distal outflow tract. Strong reporter gene expression was also noted in the mesenchyme of ventral branchial arches, and in the epithelium. In the atrioventricular canal expression was relatively lower. In the four-chambered heart stages (E13.5-E17.5) the LacZ-staining did not recapitulate the endogenous Gata3 transcript and showed rather lineage tracing of formerly Gata3-expressing cells in the hearts. beta-Galactosidase activity was detected in the cusps of semilunar valves, aorta, pulmonary trunk, innominate and common carotid arteries, and faintly in the atrioventricular valves. Gata3-null embryos die normally between E11 and E12. Pharmacological treatment with sympathomimetic beta-adrenergic receptor agonist lengthens the survival up to E18 when malformations of the heart such as ventricular septal defect (VSD), double-outlet of right ventricle (DORV), anomalies of the aortic arch (AAA) and persistent truncus arteriosus (PTA) were detected. The specified malformations correlate with the normal developmental pattern of Gata3-LacZ expression. The short outflow tract and insufficient rotation of truncus arteriosus during looping stages might be the main reasons underlying these malformations.

Twist1 Controls a Cell-Specification Switch Governing Cell Fate Decisions within the Cardiac Neural Crest

“…Collectively, Twist1 then interacts with at least five of the key SGN cell fate transcriptional regulators (Figure S9). Given that both cNCC and SGN NCC transcriptional programs are initiated by Bmp-signaling, and that these two programs, at least in part, share key transcriptional regulators (Hand1, Hand2, Gata3; [58], Sox4 [59], and (likely) Sox11 [60], [61]), it is obvious that a switch to ensure that the correct cell fate is specified and maintained is built into these developmental programs. Twist1 is a strong candidate to fulfill such a role.…”

Targeted deletion of Hand2 in cardiac neural crest-derived cells influences cardiac gene expression and outflow tract development

“…The abnormal pattern of migration, decreased cell numbers and loss of cell-cell signaling likely contribute to the formation of VSDs observed in all mutant embryos. Normal closure of the membranous septum involves three coordinated morphogenetic events: the muscular septum must grow upwards, the endocardial cushions must form the inlet septum (AV canal) and the formation of outlet septum by growth of the conotruncal ridges must occur (Webb et al, 1998; Lamers and Moorman, 2002; Raid et al, 2009). As part of this fusion, the valves are also formed.…”

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

“…It is the only hematopoietic GATA member with detectable expression in the heart as early as E9.5. Its expression is found in the endothelium of the outflow tract (OFT), in the endocardial ridges and to a lesser extent in the atrioventricular canal . Mice with reduced Gata3 expression present a variety of cardiac phenotypes including ventricular septal defects (VSDs), persistent truncus arteriosus (PTA), and anomalies of the aortic arches .…”