Folic acid prevents exencephaly in Cited2 deficient mice

Juan Pedro Martinez Barbera, Tristan A. Rodriguez, Nicholas D E Greene, Wolfgang J. Weninger, Antonio Simeone, Andrew J. Copp, Rosa S P Beddington, Sally Dunwoodie

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)283-293
Number of pages11
JournalHuman Molecular Genetics
Issue number3
Publication statusPublished - Feb 1 2002


ASJC Scopus subject areas

  • Genetics

Cite this

Martinez Barbera, J. P., Rodriguez, T. A., Greene, N. D. E., Weninger, W. J., Simeone, A., Copp, A. J., Beddington, R. S. P., & Dunwoodie, S. (2002). Folic acid prevents exencephaly in Cited2 deficient mice. Human Molecular Genetics, 11(3), 283-293.