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 exencepha ly in 10-20% of newborns. SELH/Bc mice also have a high rate of sponta neous mutation and therefore it could not be assumed that these two ab normalities share the same genetic cause. Previously, we have shown th at the liability to exencephaly in SELH/Bc mice is multifactorial, inv olving two to three loci, and that all the ataxics have a midline clef t cerebellum. The purpose of the present study was to resolve the gene tic relationship between liability to exencephaly and liability to cle ft cerebellum. We tested whether these traits were transmitted togethe r by segregating F2 males; cotransmission would indicate that both tra its are probably caused by the same genes. Approximately 100 embryos f rom 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 embryo s were scored for cleft cerebellum. The range of exencephaly productio n by these 25 F2 sires was 0% to 16%; the sires had been selected to r epresent 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 exen- cephaly al so produced some cleft cerebellum. This indicated strongly that the tw o traits are transmitted together (Fisher's exact test, P < 0.0002). F urthermore, within exencephaly-producing sires, the specific frequenci es of the two traits were significantly positively correlated (Spearma n r(s) = 0.58; P < 0.05), indicating that tile same multifactorial ris k factors influence both traits. All SELH/Bc embryos omit one normal i nitiation site of cranial neural tube closure, Closure 2. In a previou s study, absence of the Closure 2 initiation site of cranial neural tu be closure has been shown to be genetically correlated with liability to exencephaly. In the second part of the present study, the same Clos ure 2 data from eight of the F2 sires were observed to be significantl y positively correlated with liability to cleft cerebellum (Spearman r (s) = 0.83; P< 0.05). The results of this genetic approach have suppor ted the hypothesis, based on observation of embryos, that one basic mu ltifactorial genetic defect in SELH mice leads to an abnormal cranial neural tube closure mechanism, to exencephaly, to cleft cerebellum, an d to ataxia. (C) 1997 Wiley-Liss, Inc.