Journal
DEVELOPMENTAL BIOLOGY
Volume 308, Issue 2, Pages 421-437Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2007.05.037
Keywords
Msx1; Msx2; Aorticopulmonary septation; apoptosis; cardiac neural crest; conotruncus; myocardium; outflow tract malalignment; proliferation; secondary heart field
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Funding
- NIDCR NIH HHS [DE12450, DE12941] Funding Source: Medline
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Msx1 and Msx2 are highly conserved, Nk-related homeodomain transcription factors that are essential for a variety of tissue-tissue interactions during vertebrate organogenesis. Here we show that combined deficiencies of Msx] and Msx2 cause conotruncal anomalies associated with malalignment of the cardiac outflow tract (OFT). Msx1 and Msx2 play dual roles in outflow tract morphogenesis by both protecting secondary heart field (SHF) precursors against apoptosis and inhibiting excessive proliferation of cardiac neural crest, endothelial and myocardial cells in the conotruncal cushions. During incorporation of SHF precursors into the OFT myocardium, ectopic apoptosis in the Msxl-/-; Msx2-/- mutant SHF is associated with reduced expression of Hand] and Hand2, which from work on Hand I and Hand2 mutants may be functionally important in the inhibition of apoptosis in Msx]12 mutants. Later during aorticopulmonary septation, excessive proliferation in the OFT cushion mesenchyme and myocardium of Msx1-/-,- Msx2-/- mutants is associated with premature down-regulation of p27(KIPI), an inhibitor of cyclin-dependent kinases. Diminished accretion of SHF precursors to the elongating OFT myocardium and excessive accumulation of mesenchymal cells in the conotruncal cushions may work together to perturb the rotation of the truncus arteriosus, leading to OFT malalignment defects including double-outlet right ventricle, overriding aorta and pulmonary stenosis. (c) 2007 Elsevier Inc. All rights reserved.
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