Requirement of myocardin-related transcription factor-B for remodeling of branchial arch arteries and smooth muscle differentiation

Abstract

Myocardin and the myocardin-related transcription factors (MRTFs) A and B act as coactivators for serum response factor, which plays a key role in cardiovascular development. To determine the functions of MRTF-B in vivo, we generated MRTF-B mutant mice by targeted inactivation of the MRTF-B gene. We show that mice homozygous for an MRTF-B loss-of-function mutation die during mid-gestation from a spectrum of cardiovascular defects that includes abnormal patterning of the branchial arch arteries, double-outlet right ventricle, ventricular septal defects, and thin-walled myocardium. These abnormalities are accompanied by a failure in differentiation of smooth muscle cells within the branchial arch arteries, which are derived from the neural crest. The phenotype of MRTF-B mutant mice is distinct from that of mice lacking myocardin, revealing unique roles for these serum response factor coactivators in the development of different subsets of smooth muscle cells in vivo.cardiovascular development ͉ congenital heart disease ͉ heart ͉ neural crest

Myocardin‐related transcription factor B is required for normal mouse vascular development and smooth muscle gene expression

“…The MRTF-B homozygous mutant made by homologous recombination resulted in complete embryonic lethality that occurs abruptly at E14.5 (Oh et al, 2005). This time point for embryonic lethality is compatible with our data demonstrating lethality occurring in late gestation between E15.5 and the newborn stage.…”

“…Similar to previous reports, we also detected cardiac and aortic arch defects characterized by ventricular septal defects and aortic arch malformations attributed to MRTF-B deficiency Oh et al, 2005). The MRTF-B homozygous mutant made by homologous recombination resulted in complete embryonic lethality that occurs abruptly at E14.5 (Oh et al, 2005).…”

“…We expected that MRTF-B ⌬/⌬ mutant mice would succumb to heart failure and/or vascular defects given the known role of myocardin, MRTF-A, and MRTF-B as potent transcriptional activators of multiple cardiac and smooth muscle genes (Wang et al, 2001(Wang et al, , 2002Li et al, 2003;Selvaraj and Prywes, 2003;Oh et al, 2005). However, we identified no gross evidence of heart failure such as peripheral edema or pericardial effusion in any of the MRTF-B ⌬/⌬ homozygous mutant embryos.…”

“…Other gene-trap models of MRTF-B displayed perinatal lethality (Skarnes et al, 1992;Li et al, 2005). Germ-line knockout of MRTF-B resulted in earlier lethality at E13.5 that is characterized by cardiac and branchial arch defects (Oh et al, 2005). MRTF-B was shown to be important for smooth muscle differentiation of the neural crest-derived branchial arch arteries leading to a spectrum of aortic arch development defects in addition to thin myocardium and ventricular septal defects.…”

Induction and modulation of smooth muscle differentiation in Xenopus embryonic cells

“…A growing number of proteins, including GATA, MEF2, Nkx2.5 and myocardin family members have been shown to interact with SRF and modulate the transcription of target genes in a smooth muscle context (Miano, 2003). Myocardin and the myocardin-related transcription factors (MRTFs) are of particular interest because gain-and loss-of-function experiments showed that they were essential for the development and differentiation of SMC (Du et al, 2003;Li et al, 2003Li et al, , 2005Wang and Olson, 2004;Oh et al, 2005). The basic helix-loop-helix (bHLH) HAND proteins have also been implicated in the regulation of smooth muscle gene expression in mammals (Yamagishi et al, 2000;Morikawa and Cserjesi, 2004).…”