Exencephaly and cleft cerebellum in SELH/Bc mouse embryos are alternative developmental consequences of the same underlying genetic defect.

SELH/Bc inbred mice have ataxia in 5-10% of young adults and exencephaly in 10-20% of newborns. SELH/Bc mice also have a high rate of spontaneous mutation and therefore it could not be assumed that these two abnormalities share the same genetic cause. Previously, we have shown that the liability to exencephaly in SELH/Bc mice is multifactorial, involving two to three loci, and that all the ataxics have a midline cleft cerebellum. The purpose of the present study was to resolve the genetic relationship between liability to exencephaly and liability to cleft cerebellum. We tested whether these traits were transmitted together by segregating F2 males; cotransmission would indicate that both traits are probably caused by the same genes. Approximately 100 embryos from each of 25 F2 sires from a cross between SELH/Bc and the normal LM/Bc strain were scored for exencephaly and the non-exencephalic embryos were scored for cleft cerebellum. The range of exencephaly production by these 25 F2 sires was 0% to 16%; the sires had been selected to represent the extremes of the range of exencephaly production. We found that the 10 sires that produced no exencephaly also produced no cleft cerebellum and 12 of the 15 sires that produced some exencephaly also produced some cleft cerebellum. This indicated strongly that the two traits are transmitted together (Fisher's exact test, P < 0.0002). Furthermore, within exencephaly-producing sires, the specific frequencies of the two traits were significantly positively correlated (Spearman rs = 0.58; P < 0.05), indicating that the same multifactorial risk factors influence both traits. All SELH/Bc embryos omit one normal initiation site of cranial neural tube closure, Closure 2. In a previous study, absence of the Closure 2 initiation site of cranial neural tube closure has been shown to be genetically correlated with liability to exencephaly. In the second part of the present study, the same Closure 2 data from eight of the F2 sires were observed to be significantly positively correlated with liability to cleft cerebellum (Spearman rs = 0.83; P < 0.05). The results of this genetic approach have supported the hypothesis, based on observation of embryos, that one basic multifactorial genetic defect in SELH mice leads to an abnormal cranial neural tube closure mechanism, to exencephaly to cleft cerebellum, and to ataxia.