Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest.
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.
Morgan
Sarah C
SC
Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
Lee
Hyung-Yul
HY
Relaix
Frédéric
F
Sandell
Lisa L
LL
Levorse
John M
JM
Loeken
Mary R
MR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D006321:Heart / Q000196:embryology*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009432:Neural Crest / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000172:deficiency* / Q000378:metabolism; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D052160:Benzothiazoles; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D016159:Tumor Suppressor Protein p53; C068686:Pax3 protein, mouse; D014050:Toluene; C121565:pifithrin