Msx2 is an immediate downstream effector of Pax3 in the development of the murine cardiac neural crest.
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.
Kwang
Stanford J
SJ
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA.
Brugger
Sean M
SM
Lazik
Arthur
A
Merrill
Amy E
AE
Wu
Lan-Ying
LY
Liu
Yi-Hsin
YH
Ishii
Mamoru
M
Sangiorgi
Frank O
FO
Rauchman
Michael
M
Sucov
Henry M
HM
Maas
Richard L
RL
Maxson
Robert E
RE
D000818:Animals; D001483:Base Sequence; D002465:Cell Movement / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D020868:Gene Silencing; D018390:Gene Targeting; D017930:Genes, Reporter; D006321:Heart / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009432:Neural Crest / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012249:Rhombencephalon / Q000196:embryology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C084119:MSX2 protein; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C068686:Pax3 protein, mouse