Msx1 and Msx2 regulate survival of secondary heart field precursors and post-migratory proliferation of cardiac neural crest in the outflow tract

Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center and Hospital, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Developmental Biology (Impact Factor: 3.55). 09/2007; 308(2):421-37. DOI: 10.1016/j.ydbio.2007.05.037
Source: PubMed


Msx1 and Msx2 are highly conserved, Nk-related homeodomain transcription factors that are essential for a variety of tissue-tissue interactions during vertebrate organogenesis. Here we show that combined deficiencies of Msx1 and Msx2 cause conotruncal anomalies associated with malalignment of the cardiac outflow tract (OFT). Msx1 and Msx2 play dual roles in outflow tract morphogenesis by both protecting secondary heart field (SHF) precursors against apoptosis and inhibiting excessive proliferation of cardiac neural crest, endothelial and myocardial cells in the conotruncal cushions. During incorporation of SHF precursors into the OFT myocardium, ectopic apoptosis in the Msx1-/-; Msx2-/- mutant SHF is associated with reduced expression of Hand1 and Hand2, which from work on Hand1 and Hand2 mutants may be functionally important in the inhibition of apoptosis in Msx1/2 mutants. Later during aorticopulmonary septation, excessive proliferation in the OFT cushion mesenchyme and myocardium of Msx1-/-; Msx2-/- mutants is associated with premature down-regulation of p27(KIP1), an inhibitor of cyclin-dependent kinases. Diminished accretion of SHF precursors to the elongating OFT myocardium and excessive accumulation of mesenchymal cells in the conotruncal cushions may work together to perturb the rotation of the truncus arteriosus, leading to OFT malalignment defects including double-outlet right ventricle, overriding aorta and pulmonary stenosis.

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    • "been regarded as important [48]. In addition, large numbers of intermediate signals, such as Tb  20, Twist1, periostin, cadherin- 11, Sox9 and Msx1/2, are responsible for valvulogenesis [49] [50] [51] [52]. Thus, the ultimate structure of the adult valve is the result of a complex interplay between cells, matrix, cytokines and growth factors over relatively long periods. "
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    • "Gata4 deficient [72] Smad7 deficient [70] Cpsg2 deficient [73] RPP-J (Notch) deficient [74] ALK2, ALK3, BMP-2, (redundant roles of BMP-4, -5, -6, -7) deficient [75] [76] [77] [78] [79] For recent review: [80] TGFbRII deficient [81] Cx40 deficient [82] Cx45 deficient [83] CHF1/Hey1 deficient [84] Trisomy 16 deficient [85] Adm19 deficient [86] SHP2 Noonan Enlarged cushion [87] Tbx20 deficient [88] Endoglin deficient [89] twist deficient [88] [90] Sox9 deficient [91] PDK1 deficient [92] Fog2 Enlarged cushion [93] Ezh2 deficient [54] Mmp15 snail deficient [94] Msx1/2 deficient [95] Smad6 deficient [96] Slug deficient [97] Irx3,5 deficient [98] RA deficient [99] [100] [101] [102] Tbx2(misexpression in myocardium) Excess EMT [45] MAPK pathway MEKK4 deficient [103] Versican deficient [73] the ten commandments proposed by Dr Harken in order to design the best prosthetic valve [67]. The main issue in this therapeutic approach is to find the right cell population to repopulate the decellularized valve. "
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    • "In the outflow tract of the heart, Msx genes are required to inhibit excessive proliferation of post-migratory NCCs (Chen et al., 2007). In contrast, Msx genes do not seem to play a role in proliferation of the NC-derived cells that contribute to the cranial ganglia and the first pharyngeal arch, but in preventing their apoptosis (Ishii et al., 2005). "
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