Document Detail


Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract.
MedLine Citation:
PMID:  18849531     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ching-Pin Chang; Kryn Stankunas; Ching Shang; Shih-Chu Kao; Karen Y Twu; Michael L Cleary
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  135     ISSN:  0950-1991     ISO Abbreviation:  Development     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-10-13     Completed Date:  2008-12-31     Revised Date:  2011-09-26    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  3577-86     Citation Subset:  IM    
Affiliation:
Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA. chingpin@stanford.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Arteries / cytology,  embryology*,  metabolism
Body Patterning / genetics*
Branchial Region / blood supply,  cytology,  embryology,  metabolism
Cell Movement
Embryo, Mammalian / cytology,  metabolism
Gene Expression Regulation, Developmental
Gene Regulatory Networks*
Heart / anatomy & histology*,  embryology*
Homeodomain Proteins / genetics,  metabolism*
Mice
Models, Biological
Myocardium / cytology,  metabolism
Neural Crest / cytology,  metabolism
Paired Box Transcription Factors / genetics,  metabolism
Promoter Regions, Genetic
Transcription Factors / deficiency,  genetics,  metabolism*
Transcription, Genetic
Grant Support
ID/Acronym/Agency:
CA42971/CA/NCI NIH HHS; CA90735/CA/NCI NIH HHS; HL085345/HL/NHLBI NIH HHS; R01 CA090735-08/CA/NCI NIH HHS; R01 HL085345-03/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Homeodomain Proteins; 0/MSX2 protein; 0/Paired Box Transcription Factors; 0/Pbx1 protein, mouse; 0/Transcription Factors; 138016-91-8/Pax3 protein, mouse
Comments/Corrections

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