Abstract
BackgroundMsx1 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.ResultsWhile 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.ConclusionOur findings demonstrate redundant roles of Msx1 and Msx2 in regulating signals required for development of the AV myocardium and formation of the AV valves.
Highlights
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
Several signaling molecules have been implicated in regulating endothelial-mesenchymal transformation (EMT) during cardiac valve formation, including the Nuclear Factor in Activated T cells (NFAT) [9,10,11,12], Vascular Endothelial Growth Factor (VEGF) [11,13], and members of the Epidermal Growth Factor (EGF) [1,6,14,15], Bone Morphogenetic Protein (Bmp) [16,17,18,19], Notch [20,21,22], Transforming Growth Factor-β (TGF-β) [4,18,19,23], and Wnt/β-catenin families [24,25]
To evaluate the functional redundancy of Msx1 and Msx2 in AV cushion morphogenesis, we examined expression patterns of Msx1 and Msx2 in the AV canal (AVC) between E9.5 and E11.5, while EMT of the endocardial cushions was actively taking place [4,16,18]
Summary
Msx and Msx, 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. Msx and Msx have well-documented roles in mediating epithelial-mesenchymal interactions during organogenesis Given that both Msx and Msx are crucial downstream effectors of Bmp signaling, we investigated whether Msx and Msx are required for the Bmp-induced endothelial-mesenchymal transformation (EMT) during atrioventricular (AV) valve formation. (OFT) are formed through an endothelial-mesenchymal transformation (EMT), a remarkably complex event initiated by the specification and activation of a subset of endothelial cells in the cushion-forming regions. This event is followed by cell delamination from the endocardium and cell migration into the extracellular matrix between the endocardium and myocardium (referred to as the cardiac jelly) [4,5,6]. Several signaling molecules have been implicated in regulating EMT during cardiac valve formation, including the Nuclear Factor in Activated T cells (NFAT) [9,10,11,12], Vascular Endothelial Growth Factor (VEGF) [11,13], and members of the Epidermal Growth Factor (EGF) [1,6,14,15], Bone Morphogenetic Protein (Bmp) [16,17,18,19], Notch [20,21,22], Transforming Growth Factor-β (TGF-β) [4,18,19,23], and Wnt/β-catenin families [24,25]
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