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Development 129, 527-538 (2002)
© 2002 The Company of Biologists Limited

Msx2 is an immediate downstream effector of Pax3 in the development of the murine cardiac neural crest

Stanford J. Kwang1,*, Sean M. Brugger2,*, Arthur Lazik2,*, Amy E. Merrill2, Lan-Ying Wu2, Yi-Hsin Liu1, Mamoru Ishii2, Frank O. Sangiorgi1, Michael Rauchman3, Henry M. Sucov2, Richard L. Maas4 and Robert E. Maxson, Jr.2,{dagger}

1 Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA
2 Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA
3 Department of Medicine, Renal Division, School of Medicine, Washington University, St Louis, MO 63110, USA
4 Genetics Division, Department of Medicine, Brigham and Women’s Hospital and Harvard, Medical School, Harvard University, Boston, MA 02115, USA
* These authors contributed equally to the experimental work

{dagger}Author for correspondence (e-mail: maxson{at}hsc.usc.edu)

Accepted 24 October 2001

The neural crest plays a crucial part in cardiac development. Cells of the cardiac subpopulation of cranial neural crest migrate from the hindbrain into the outflow tract of the heart where they contribute to the septum that divides the pulmonary and aortic channels. In Splotch mutant mice, which lack a functional Pax3 gene, migration of cardiac neural crest is deficient and aorticopulmonary septation does not occur. Downstream genes through which Pax3 regulates cardiac neural crest development are unknown. Here, using a combination of genetic and molecular approaches, we show that the deficiency of cardiac neural crest development in the Splotch mutant is caused by upregulation of Msx2, a homeobox gene with a well-documented role as a regulator of BMP signaling. We provide evidence, moreover, that Pax3 represses Msx2 expression via a direct effect on a conserved Pax3 binding site in the Msx2 promoter. These results establish Msx2 as an effector of Pax3 in cardiac neural crest development.

Key words: Cardiac neural crest, Knockout, Mouse, Msx1, Msx2, Pax3, Splotch


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© The Company of Biologists Ltd 2002