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Human Molecular Genetics, 2000, Vol. 9, No. 4 575-581
© 2000 Oxford University Press

A genetic risk factor for mouse neural tube defects: defining the embryonic basis

Angeleen Fleming+ and Andrew J. Copp§

Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK

Genetic polymorphisms are thought to play an important role in determining susceptibility to neural tube defects (NTDs), for example between different ethnic groups, but the embryonic manifestation of these polymorphic genetic influences is unclear. We have used a mouse model to test experimentally whether polymorphic variations in the pattern of cranial neural tube closure can influence susceptibility to NTDs. The site at which cranial neural tube closure begins (so-called closure 2) is polymorphic between inbred mice. Strains with a caudal location of closure 2 (e.g. DBA/2) are relatively resistant to NTDs, whereas strains with a rostrally positioned closure 2 (e.g. NZW) exhibit increased susceptibility to NTDs. We tested experimentally whether altering the position of closure 2 can affect susceptibility to cranial NTDs, by back- crossing the splotch (Sp2H) mutant gene onto the DBA/2 background. As a control, Sp2H was transferrred onto the NZW background, which resembles splotch mice in its closure pattern. Approximately 80% of Sp2H homozygotes develop NTDs, both cranial (exencephaly) and spinal (spina bifida). After transfer to the DBA/2 background, the frequency of cranial NTDs was reduced significantly in Sp2H homozygotes, confirming a protective effect of caudal closure 2. In contrast, Sp2H homozygotes on the NZW background had a persistently high frequency of cranial NTDs. The frequency of spina bifida was not altered in either backcross, emphasizing the specificity of this genetic effect for cranial neurulation. These findings demonstrate that variation in the pattern of cranial neural tube closure is a genetically determined factor influencing susceptibility to cranial NTDs.

+ Present address: Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK

§ To whom correspondence should be addressed. Tel: +44 171 829 8893; Fax: +44 171 831 4366; Email: a.copp@ich.ucl.ac.uk


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