Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
Mechanisms of development (Impact Factor: 2.44). 09/2008; 125(9-10):757-67. DOI: 10.1016/j.mod.2008.07.003
Source: PubMed


During neural tube closure, Pax3 is required to inhibit p53-dependent apoptosis. Pax3 is also required for migration of cardiac neural crest (CNC) from the neural tube to the heart and septation of the primitive single cardiac outflow tract into the aorta and pulmonary arteries. Whether Pax3 is required for CNC migration and outflow tract septation by inhibiting p53-dependent apoptosis is not known. In this study, mouse strains carrying reporters linked to Pax3 alleles were used to map the fate of CNC cells in embryos which were either Pax3-sufficient (expressing one or two functional Pax3 alleles) or Pax3-deficient (expressing two null Pax3 alleles), and in which p53 had been inactivated or not. Migrating CNC cells were observed in both Pax3-sufficient and -deficient embryos, but CNC cells were sparse and disorganized in Pax3-deficient embryos as migration progressed. The defective migration was associated with increased cell death. Suppression of p53, either by null mutation of the p53 gene, or administration of a p53 inhibitor, pifithrin-alpha, prevented the defective CNC migration and apoptosis in Pax3-deficient embryos, and also restored proper development of cardiac outflow tracts. These results indicate that Pax3 is required for cardiac outflow tract septation because it blocks p53-dependent processes during CNC migration.


Available from: Mary R Loeken
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    • "Via the Wnt/Fz/Dvl pathway, DAAM1 with RhoA participates in morphology and migratory behaviors in vertebrates such as cell fate specification, migration, proliferation and apoptosis [13,17]. Cardiac neural crest (cNC) passes through pharyngeal arches to the efferent pathway of the heart, and subsequent directional cell migration are essential for the formation of cardiac outflow tract [18]. Failure of the cNC directed migration may cause severe defects in the conotruncal region and the atrioventricular septum. "
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    • "Mesenchymal cells were counted and divided by the total number of cells in a 40 field of view from three different regions of the cultures. -galactosidase staining was quantified as previously described (Morgan et al., 2008). Epicardial differentiation of smooth muscle cells was quantified following immunostaining against SM- MHC. "
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    • "This suggests that the ensuing NTD and COTD result from depletion of progenitor cells that are necessary to populate these structures. We showed that inactivation of p53 through germ-line mutation or chemical inhibition prevented the NTD, exencephaly and spina bifida, and COTD that are characteristic of Pax3Sp/Sp embryos, as well as associated apoptosis, in embryos expressing nonfunctional Pax3 alleles [25], [27]. This indicates that Pax3 is not required in neuroepithelium and neural crest to regulate genes that direct morphogenesis or migration, but that it is required to block p53-dependent processes that lead to apoptosis. "
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