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Multifactorial genetics of exencephaly in the SELH/Bc mouse strain Hoscheit, Julia Lynn


The SELH/Bc mouse strain, a model for multifactorial human neural tube defects, has 10-30% exencephaly depending on the maternal diet. Developmental morphological studies have found that the mesencephalon fold elevation is delayed, compared to other normal strains, in all SELH/Bc embryos and that they omit Closure 2, a normal site of initiation of closure at the mesencephalon/prosencephalon boundary during cranial neural tube closure. Previous studies have found the genetic exencephaly risk to be due to a combination of three genes, Exen1, Exen2, and Exen3, acting additively. Exen1 and Exen2 had been mapped to regions on Chr 13 and Chr 5, respectively, and Exen3 provisionally to Chr 11. My studies further investigated the genetic cause of this defect using F2 exencephaly panels and congenic lines, as well as the diet effect that is observed in SELH/Bc. The frequencies of exencephaly were observed in F2 segregants from crosses between SELH/Bc and a normal unrelated strain, LM/Bc. There were two F2 exencephaly panels collected, one from mice fed the regular diet Purina Laboratory Rodent Diet #5001 and one from mice fed the high-risk diet Purina Mouse Diet #5015 ("PMD #5015") that increases exencephaly frequency in SELH/Bc. There was a significant increase in exencephaly frequency in the F2 embryos when mice were fed PMD #5015 and genotypes of the F2 ex encephalic embryos from both panels supported the hypothesis that there is gene-diet interaction between the Exen1 alleles from SELH/Bc and PMD #5015. A new locus on Chr 7 that contributed to the risk of exencephaly in the F2 embryos, named Exen4, was established as well. The congenic lines that had been created by transferring the normal Exen1 and Exen2 alleles from LM/Bc into the SELH/Bc background and the Exen1 and Exen2 alleles from SELH/Bc into the LM/Bc background confirmed the locations of the Exenl and Exen2 loci, and demonstrated that exencephaly in SELH/Bc is a multifactorial threshold trait. The congenic lines with Exen1 alleles from SELH/Bc responded to PMD #5015 supporting the hypothesis of a gene-diet interaction. Morphological studies of the cranial neural tube closure patterns in congenic line embryos supported the hypothesis that the liability trait for exencephaly (multifactorial threshold defect) is timing of mesencephalon fold elevation as the congenic line embryos showed detectable delay or acceleration of elevation of mesencephalon folds compared to their respective parental strain.

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