Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract.
The patterning of the cardiovascular system into systemic and pulmonic circulations is a complex morphogenetic process, the failure of which results in clinically important congenital defects. This process involves extensive vascular remodeling and coordinated division of the cardiac outflow tract (OFT). We demonstrate that the homeodomain transcription factor Pbx1 orchestrates separate transcriptional pathways to control great-artery patterning and cardiac OFT septation in mice. Pbx1-null embryos display anomalous great arteries owing to a failure to establish the initial complement of branchial arch arteries in the caudal pharyngeal region. Pbx1 deficiency also results in the failure of cardiac OFT septation. Pbx1-null embryos lose a transient burst of Pax3 expression in premigratory cardiac neural crest cells (NCCs) that ultimately specifies cardiac NCC function for OFT development, but does not regulate NCC migration to the heart. We show that Pbx1 directly activates Pax3, leading to repression of its target gene Msx2 in NCCs. Compound Msx2/Pbx1-null embryos display significant rescue of cardiac septation, demonstrating that disruption of this Pbx1-Pax3-Msx2 regulatory pathway partially underlies the OFT defects in Pbx1-null mice. Conversely, the great-artery anomalies of compound Msx2/Pbx1-null embryos remain within the same spectrum as those of Pbx1-null embryos. Thus, Pbx1 makes a crucial contribution to distinct regulatory pathways in cardiovascular development.
Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA. chingpin@stanford.edu
Ching-Pin
CP
Chang
Kryn
K
Stankunas
Ching
C
Shang
Shih-Chu
SC
Kao
Karen Y
KY
Twu
Michael L
ML
Cleary
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics*; D001934:Branchial Region / Q000098:blood supply / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006321:Heart / Q000033:anatomy & histology* / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D018398:Homeodomain Proteins; C084119:MSX2 protein; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors; C068686:Pax3 protein, mouse