title: RestrictedPax3Deletion within the Neural Tube Results in Congenital Hydrocephalus.
abstract: Congenital hydrocephalus is a common birth-defect whose developmental origins are poorly understood.Pax3-null mutants show defects in myogenesis, neural tube closure, neural crest morphogenesis, and heart development that, consequently, results in embryonic lethality. Here we demonstrate that conditional deletion of the mousePax3transcription factor results in fully-penetrant congenital obstructive hydrocephalus. To identify the role of Pax3 during cranial development, we deletedPax3within the neuroepithelium (viaPax7-Cre), in the neural crest (viaP0-Cre), and in both the neuroepithelium and the neural crest (viaWnt1-Cre). Only conditional mutants generated usingPax7-CreorWnt1-Credeveloped early onset congenital hydrocephalus due to stenosis of the third ventricle, suggesting that loss of neuroepithelial Pax3 is sufficient to disturb third ventricle morphogenesis. Dilation of lateral ventricles occurs as early as E14.5, and lineage-mapping revealed that the neuroepithelial cells in the conditional mutants are present, but fail to undergo normal differentiation at the stenotic site. Concomitant with a narrowing of the mutant third ventricle, we detected ectopic apoptosis, reduced proliferation, and abnormal β-catenin localization. Furthermore, consistent with the overlapping expression pattern of Pax3 and Pax7 in early cranial neuroepithelium, we demonstrated a combinatorial role, as compoundPax3/Pax7heterozygotes display partially-penetrant congenital hydrocephalus. These murine data provide an experimental paradigm underpinning clinical observations of the presence of PAX3 mutations in some hydrocephalic patients.
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, IN 46202, USA.
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Zhou
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, IN 46202, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
keywords: Pax3; Pax7; congenital hydrocephalus; lineage mapping; mouse embryo; neural tube defects