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Genetic and developmental studies of abnormal neural tube closure in SELH/Bc mice

University of British Columbia

The SELH/Bc mouse strain produces the lethal cranial neural tube defect, exencephaly, in 10-20% of embryos and newborns and is a model for multifactorial human neural tube defects. The mesencephalic folds of all SELH/Bc embryos fail to elevate and make contact at Closure 2, a normal site of initiation of closure at the prosencephalon/ mesencephalon boundary. The cause of this defect was investigated. Histology of the cranial neural folds of early (3-11 somite) SELH/Bc embryos showed that morphological abnormalities are present as early as the 3-somite stage. Divergence of the folds from the neural groove was more angular and the lateral tips were consistently less elevated than in normal embryos. However, the primary defect was not obvious. The hypothesis that there is a defect in the cytoskeleton of neuroepithelial cells was tested, but not supported, as actin microfilament distribution was normal in 7-somite SELH/Bc embryos. The frequencies of exencephaly observed in F l , BC1, F2, and F2-testcross progeny from a cross between the SELH/Bc and LM/Bc (normal) strains suggested segregation of 2-3 additive exencephaly-liability loci. The genetic liability to exencephaly of 102 F2 sires (based on frequency produced in 100 testcross progeny each) was determined, and linkage of genetic markers to the exencephaly trait in 10 high-risk sires (produced the highest frequencies of exencephaly) and 10 low-risk sires (produced no exencephaly) was tested. Analysis suggested liability loci on chromosomes 10 and 13, and a suppressor locus in SELH/Bc on chromosome 2. Mapping in these regions was tested in exencephalic F2 embryos, where evidence of a liability locus was strong for chromosome 13, suggestive for chromosome 2, and weak for chromosome 10. The panel of testcrossed F2 sires was used to test the hypothesis that lack of Closure 2 causes exencephaly, by demonstrating co-segregation of these traits in testcross progeny of high- and low-risk F2 sires. In addition, the hypothesis that liability to cleft cerebellumataxia, a trait observed in 5-10% of weaned SELH/Bc mice, shares a common genetic basis with liability to exencephaly was supported as low-risk sires produced neither trait and highrisk sires produced high frequencies of both.

Thesis/Dissertation

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2009-02-20

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http://hdl.handle.net/2429/4833

Genetics

University of British Columbia

UBCV

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