Ets1 is required for proper migration and differentiation of the cardiac neural crest. Development 2010 May;137(9):1543-51
Date
04/02/2010Pubmed ID
20356956Pubmed Central ID
PMC2853851DOI
10.1242/dev.047696Scopus ID
2-s2.0-77951236294 (requires institutional sign-in at Scopus site) 67 CitationsAbstract
Defects in cardiac neural crest lead to congenital heart disease through failure of cardiac outflow tract and ventricular septation. In this report, we demonstrate a previously unappreciated role for the transcription factor Ets1 in the regulation of cardiac neural crest development. When bred onto a C57BL/6 genetic background, Ets1(-/-) mice have a nearly complete perinatal lethality. Histologic examination of Ets1(-/-) embryos revealed a membranous ventricular septal defect and an abnormal nodule of cartilage within the heart. Lineage-tracing experiments in Ets1(-/-) mice demonstrated that cells of the neural crest lineage form this cartilage nodule and do not complete their migration to the proximal aspects of the outflow tract endocardial cushions, resulting in the failure of membranous interventricular septum formation. Given previous studies demonstrating that the MEK/ERK pathway directly regulates Ets1 activity, we cultured embryonic hearts in the presence of the MEK inhibitor U0126 and found that U0126 induced intra-cardiac cartilage formation, suggesting the involvement of a MEK/ERK/Ets1 pathway in blocking chondrocyte differentiation of cardiac neural crest. Taken together, these results demonstrate that Ets1 is required to direct the proper migration and differentiation of cardiac neural crest in the formation of the interventricular septum, and therefore could play a role in the etiology of human congenital heart disease.
Author List
Gao Z, Kim GH, Mackinnon AC, Flagg AE, Bassett B, Earley JU, Svensson ECMESH terms used to index this publication - Major topics in bold
AggrecansAnimals
Blotting, Western
Butadienes
Cartilage
Cell Differentiation
Cell Movement
Chondrocytes
Enzyme Inhibitors
Fluorescent Antibody Technique
Heart
Heart Defects, Congenital
In Situ Hybridization
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Neural Crest
Nitriles
Proto-Oncogene Protein c-ets-1
Reverse Transcriptase Polymerase Chain Reaction
SOX9 Transcription Factor
SOXD Transcription Factors
