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Human Molecular Genetics, 2002, Vol. 11, No. 3 283-293
© 2002 Oxford University Press

Folic acid prevents exencephaly in Cited2 deficient mice

Juan Pedro Martinez Barbera1,2,+, Tristan A. Rodriguez2, Nicholas D. E. Greene3, Wolfgang J. Weninger4, Antonio Simeone1, Andrew J. Copp3, Rosa S. P. Beddington2 and Sally Dunwoodie2,5

1MRC Centre for Developmental Neurobiology, 4th floor New Hunt’s House, King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, UK, 2National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK, 3Neural Development Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, 4Department of Anatomy, University of Vienna, Waehringerstrasse 13, A-1090, Vienna, Austria and 5Developmental Biology Unit, Victor Chang Cardiac Research Institute, St Vincent’s Hospital, 384 Victoria Street, Darlinghurst, NSW 2010, Australia

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.

+ To whom correspondence should be addressed. Tel: +44 207 848 6536; Fax: +44 207 848 6550; Email: juan.martinez-barbera@kcl.ac.uk This article is dedicated to Rosa Beddington, an extraordinary scientist and a wonderful friend


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