Msx1 and Msx2 are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium.
BACKGROUND
Msx1 and Msx2, which belong to the highly conserved Nk family of homeobox genes, display overlapping expression patterns and redundant functions in multiple tissues and organs during vertebrate development. Msx1 and Msx2 have well-documented roles in mediating epithelial-mesenchymal interactions during organogenesis. Given that both Msx1 and Msx2 are crucial downstream effectors of Bmp signaling, we investigated whether Msx1 and Msx2 are required for the Bmp-induced endothelial-mesenchymal transformation (EMT) during atrioventricular (AV) valve formation.


RESULTS
While both Msx1-/- and Msx2-/- single homozygous mutant mice exhibited normal valve formation, we observed hypoplastic AV cushions and malformed AV valves in Msx1-/-; Msx2-/- mutants, indicating redundant functions of Msx1 and Msx2 during AV valve morphogenesis. In Msx1/2 null mutant AV cushions, we found decreased Bmp2/4 and Notch1 signaling as well as reduced expression of Has2, NFATc1 and Notch1, demonstrating impaired endocardial activation and EMT. Moreover, perturbed expression of chamber-specific genes Anf, Tbx2, Hand1 and Hand2 reveals mispatterning of the Msx1/2 double mutant myocardium and suggests functions of Msx1 and Msx2 in regulating myocardial signals required for remodelling AV valves and maintaining an undifferentiated state of the AV myocardium.


CONCLUSIONS
Our findings demonstrate redundant roles of Msx1 and Msx2 in regulating signals required for development of the AV myocardium and formation of the AV valves.
Chen
Yi-Hui
YH
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9176, USA. yihuiche@gate.sinica.edu.tw
Ishii
Mamoru
M
Sucov
Henry M
HM
Maxson
Robert E
RE
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019521:Body Patterning; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology; D054089:Endocardial Cushions / Q000166:cytology / Q000196:embryology*; D004699:Endocardium / Q000166:cytology / Q000196:embryology; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006351:Heart Valves / Q000166:cytology / Q000196:embryology; D018398:Homeodomain Proteins / Q000235:genetics*; D051957:MSX1 Transcription Factor / Q000235:genetics*; D008648:Mesoderm / Q000166:cytology / Q000196:embryology; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000166:cytology*; D050778:NFATC Transcription Factors / Q000235:genetics; D038081:Organogenesis; D051881:Receptor, Notch1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D050778:NFATC Transcription Factors; D051881:Receptor, Notch1; D016212:Transforming Growth Factor beta; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; C095572:Hand1 protein, mouse; C084119:MSX2 protein; C484084:Msx1 protein, mouse; C494005:Nfatc1 protein, mouse; C497762:Notch1 protein, mouse