Apaf-1 deficiency and neural tube closure defects are found in fog mice

The forebrain overgrowth mutation (fog) was originally described as a spont aneous autosomal recessive mutation mapping to mouse chromosome 10 that pro duces forebrain defects, facial defects, and spina bifida. Although the fog mutant has been characterized and available to investigators for several y ears, the underlying mutation causing the pathology has not been known. Bec ause of its phenotypic resemblance to apoptotic protease activating factor- 1 (Apaf-1) knockout mice, we have investigated the possibility that the fog mutation is in the Apaf-1 gene. Allelic complementation, Western blot anal ysis, and caspase activation assays indicate that fog mutant mice lack Apaf -1 activity. Northern blot and reverse transcription-PCR analysis show that Apaf-1 mRNA is aberrantly processed, resulting in greatly reduced expressi on levels of normal Apaf-1 mRNA. These findings are strongly suggestive of the fog mutation being a hypomorphic Apaf-1 defect and implicate neural pro genitor cell death in the pathogenesis of spina bifida-a common human conge nital malformation. Because a complete deficiency in Apaf-1 usually results in perinatal lethality and fog/fog mice more readily survive into adulthoo d, these mutants serve as a valuable model with which apoptotic cell death can be studied in vivo.