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Myocardin-Related Transcription Factor B Is Required in Cardiac Neural Crest for Smooth Muscle Differentiation and Cardiovascular Development

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Myocardin-Related Transcription Factor B Is Required in Cardiac Neural Crest for Smooth Muscle Differentiation and Cardiovascular Development Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development Jian Li, Xiaohong Zhu, Mary Chen, Lan Cheng, Deying Zhou, Min Min Lu, Kevin Du, Jonathan A. Epstein, and Michael S. Parmacek* Penn Cardiovascular Institute, Molecular Cardiology Research Center, University of Pennsylvania, Philadelphia, PA 19104 Communicated by Mark T. Keating, Harvard Medical School, Boston, MA, May 6, 2005 (received for review March 30, 2005) Members of the myocardin-related family of transcription factors ogies involving the cardiac outflow tract and great arteries that play critical roles in regulating vascular smooth muscle and cardiac are associated with common forms of congenital heart disease differentiation. To examine the function of myocardin-related observed in humans (5). transcription factor (MRTF)-B, mice were generated from ES cells A critical step in the formation of the cardiac outflow tract and harboring a conditional insertional mutation, or gene trap, of the of the great arteries is the differentiation of neural crest cells to MRTF-B gene. Expression of the MRTF-B mutant allele results in a specified SMCs. Relatively little is currently understood about fusion protein consisting of the N terminus of MRTF-B fused to the molecular mechanisms regulating differentiation of SMCs ␤-galactosidase, which is functionally null. Homozygous MRTF-B from neural crest progenitors. By contrast, SMCs arising from gene trap mice (MRTF-B؊/؊) die between embryonic day (E)17.5 lateral mesoderm and local mesenchyme are regulated by a and postnatal day 1 from cardiac outflow tract defects. MRTF-B is serum response factor (SRF)-dependent transcriptional regula- expressed in the premigratory neural crest, in rhombomeres 3 and tory program (6). SRF activates SMC transcription regulatory 5, and in the neural crest-derived mesenchyme surrounding the elements by physically associating with the SMC- and cardiac- aortic arch arteries. Consistent with the pattern of expression, restricted transcriptional coactivator myocardin (7–9). Mice E10.5 and E11.5 MRTF-B؊/؊ mutants exhibit deformation of aortic harboring a myocardin null mutation die at embryonic day arch arteries 3, 4, and 6 and severe attenuation of smooth muscle (E)10.5 and show no evidence of vascular SMC differentiation cell differentiation in the arch arteries and the aorticopulmonary in the dorsal aorta (10). It remains unclear whether identical, septum, despite normal migration and initial patterning of cardiac overlapping, or distinct transcriptional programs regulate dif- neural crest cells. Remarkably, the observed pathology was res- ferentiation of SMCs arising from the lateral mesoderm and cued and viable mice generated by intercrossing MRTF-B mutants cardiac neural crest. However, the finding that common forms of with mice expressing Cre recombinase under the transcriptional congenital heart disease involving neural crest-derived struc- control of the neural crest-restricted Wnt-1 promoter, which results tures are generally not associated with other vascular malfor- in restoration of normal MRTF-B expression in the neural crest. mations suggests that the developmental programs regulating Taken together, these studies reveal that MRTF-B plays a critical these processes are distinct. role in regulating differentiation of cardiac neural crest cells into Two myocardin-related transcription factors (MRTFs), des- smooth muscle and demonstrate that neural crest-derived smooth ignated MRTF-A and -B, have been described (11). Like myo- muscle differentiation is specifically required for normal cardio- cardin, these factors physically associate with SRF and activate vascular morphogenesis. SMC-restricted transcription. MRTF-A is expressed by multiple cell lineages and is a remarkably potent transcriptional coacti- congenital heart disease ͉ myocardin ͉ heart ͉ angiogenesis vator of some SRF-dependent genes (11–15). In response to RhoA-mediated and cytoskeletal signals, MRTF-A translocates he critical role that the cardiac neural crest plays in the from the cytoplasm to the nucleus and activates gene expression Tmorphogenetic program regulating cardiac outflow tract (12–14). By contrast, relatively little is currently understood development and formation of the great arteries has been about the function of MRTF-B, which is expressed in a unique revealed through classical anatomic neural crest ablation exper- developmentally regulated lineage-restricted fashion, including iments in combination with quail–chick cell transplantation expression in some SMCs and the heart (11). Compared with studies (1, 2). Recently, the application of genetic Cre-Lox myocardin and MRTF-A, the full length MRTF-B protein is a fate-mapping techniques and the generation of mouse models relatively weak transcriptional coactivator, although it contains recapitulating human congenital heart disease have begun to a powerful transcriptional activation domain (11). Of note, define the molecular basis of cardiac outflow tract development complete inhibition of RhoA-inducible SRF-mediated gene (3, 4). Neural crest cells arising in the dorsal neural tube between expression requires blockade of both MRTF-A and -B, suggest- the midotic placode and the third somite contribute to portions ing some redundancy of function between MRTF-A and -B (15). of the heart and great vessels leading to their designation as the Materials and Methods cardiac neural crest (1). In response to poorly understood Generation and Characterization of MRTF-B Gene Trap Mice. ES cells developmental cues, these cells migrate ventrally, populating the containing an insertional mutation or gene trap in the MRTF-B aortic arch arteries and cardiac outflow tract. The neural crest gene (clone RRJ478) were provided by BayGenomics, which can derivatives then differentiate into smooth muscle cells (SMCs) be accessed at http:͞͞baygenomics.ucsf.edu. The gene-trap vec- forming the tunica media of the great arteries and the ascending aorta (1). Concomitant with this migration, two advancing columns of neural crest cells invade the cardiac outflow tract Abbreviations: SMCs, smooth muscle cells; SRF, serum response factor; En, embryonic day where they fuse, dividing the single great vessel, the truncus n; MRTF, myocardin-related transcription factor; Pn, postnatal day n. arteriosus, forming the aorticopulmonary septum and establish- *To whom correspondence should be addressed. E-mail: michael.parmacek@uphs. ing the aorta and pulmonary arteries (1). Alterations in this upenn.edu. complex developmental program lead to a spectrum of pathol- © 2005 by The National Academy of Sciences of the USA 8916–8921 ͉ PNAS ͉ June 21, 2005 ͉ vol. 102 ͉ no. 25 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0503741102 Downloaded by guest on October 2, 2021 Fig. 1. Characterization of MRTF-B gene trap mice. (A) Schematic representation of the MRTF-B gene trap. (Top) The gene trap vector contains a splice acceptor (SA) sequence flanked by loxP sites (triangles) subcloned 5Ј of the ␤geo cassette and a polyadenylation sequence (pA). (Middle) A partial restriction map of the mouse MRTF-B gene showing exon 10 and 11 sequences (rectangles). PCR primers are shown (arrows). (Bottom) A partial restriction map of the MRTF-B mutated allele. (B) Southern blot analysis of DNA prepared from the offspring of MRTF-Bϩ/Ϫ ϫ MRTF-Bϩ/Ϫ mating. The positions of the wild-type (9.8-kb) and mutant (6.5-kb) alleles are indicated to the left. (C) Northern blot analyses of MRTF-B gene expression in wild-type (ϩ͞ϩ), heterozygous (ϩ͞Ϫ), and null (Ϫ͞Ϫ) MRTF-B embryos. RNA was harvested from E12.5 embryos. The wild-type (9.5-kb) and mutant (7.5-kb) transcripts are shown to the left. (D) Real-time RT-PCR of MRTF-B gene expression in wild-type (ϩ͞ϩ), heterozygous (ϩ͞Ϫ), and null (Ϫ͞Ϫ) MRTF-B embryos. (E) MRTF-A- and –B-induced transactivation of the SM22␣ promoter in NIH 3T3 cells. NIH 3T3 cells were cotransfected with the indicated amounts (in micrograms) of expression plasmids and p-441SM22.luc. The data are presented as relative luciferase activities Ϯ SEM. (F) Forced expression of the MRTF-B⌬731 mutant protein does not repress myocardin-induced transactivation of the SM22␣ promoter in NIH 3T3 cells. NIH 3T3 cells were cotransfected with the indicated amounts (␮g) of expression plasmid and p-441SM22.luc. tor (pGT0 lxf) contains a splice-acceptor sequence flanked by described previously (9, 13). NIH 3T3 cells were cotransfected loxP sites (floxed) subcloned 5Ј of the ␤geo reporter cassette with 200 ng of the indicated luciferase reporter plasmid, 100–500 encoding a fusion protein consisting of the bacterial lacZ gene ng of the indicated expression plasmid, and 10 ng of the fused to neomycin phosphotransferase II (16). DNA sequence phRL-TK (-Int) reference plasmid (Promega), as described (18). analysis revealed that the floxed splice acceptor and ␤-geo cassette integrated 191 bp 3Ј of MRTF-B exon 10 generating Immunohistochemistry and in Situ Hybridization Analyses. Immuno- truncated MRTF-B lacking a transcriptional activation domain histochemistry and in situ hybridization protocols are available (Fig. 1A). Clone RRJ478 ES cells were injected into blastocysts at www.uphs.upenn.edu͞mcrc͞histology͞histologyhome.html from C57BL͞6J mice, and mutant mice were generated and (19). Antibodies included: anti-MF20 monoclonal antibody (De- characterized as described (17). To rescue MRTF-BϪ/Ϫ mice velopmental Studies Hybridoma Bank, Iowa City, IA); anti- specifically in
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