title: Folic acid prevents exencephaly in Cited2 deficient mice.
abstract: Cited2 (also Mrg1/p35srj) is a member of a new conserved gene family that is expressed during mouse development and in adult tissues. In order to investigate the function of Cited2 during mouse embryogenesis, we introduced a null mutation into the Cited2 locus. Cited2(-/-) mutants died at late gestation and exhibited heart defects and exencephaly, arising from defective closure of the midbrain (MB) and hindbrain. Initiation of neural tube closure at the forebrain-midbrain (FB-MB) boundary, an essential step for closure of the cranial neural tube, was impaired in the Cited2(-/-) mutants. Gene marker analysis using in situ hybridization revealed that the patterning of the anterior neural plate and head mesenchyme was little affected or normal in the Cited2(-/-) embryos. However, Cited2 was required for the survival of neuroepithelial cells and its absence led to massive apoptosis in dorsal neuroectoderm around the FB-MB boundary and in a restricted transverse domain in the hindbrain. Treatment with folic acid significantly reduced the exencephalic phenotype in the Cited2(-/-) embryos both in vivo and in vitro. However, assessment of folate metabolism revealed no defect in the Cited2(-/-) mutants, and the elevated apoptosis observed in the neuroepithelium of the Cited2(-/-) mutants was apparently not decreased by folic acid supplementation. To our knowledge, the Cited2 mouse represents the first genetic model in which folic acid can prevent a defect in neural tube closure by a mechanism other than the neutralization of a defect in folate homeostasis.
authors.affiliation: MRC Centre for Developmental Neurobiology, 4th floor New Hunt's House, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK. juan.martinez-barbera@kcl.ac.uk
authors.forename: Juan Pedro Martinez
authors.initials: JP
authors.lastname: Barbera
authors.forename: Tristan A
authors.initials: TA
authors.lastname: Rodriguez
authors.forename: Nicholas D E
authors.initials: ND
authors.lastname: Greene
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Weninger
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
authors.forename: Rosa S P
authors.initials: RS
authors.lastname: Beddington
authors.forename: Sally
authors.initials: S
authors.lastname: Dunwoodie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004475:Ectoderm / Q000502:physiology; D005313:Fetal Death; D005492:Folic Acid / Q000494:pharmacology*; D005822:Genetic Vectors; D005838:Genotype; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics* / Q000517:prevention & control; D012097:Repressor Proteins; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
chemical_list: C110087:Cited2 protein, mouse; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D005492:Folic Acid