Apaf1 reduced expression levels generate a mutant phenotype in adult brain and skeleton

Apoptosis plays a major role in the morphogenesis and homeostasis of the developing central nervous system (CNS). The apoptosome, activated during development and in the adult brain, is the dynamic effector of the mitochondrial pathway of cell death. The adapter molecule Apaf1 (apoptotic protease activating factor 1) is the core of the apoptosome.^1,2,3 Pro-apoptotic molecules such as Bax and Bid and anti-apoptotic molecules such as Bcl-X_L or Bcl-2 regulate, upon specific stimuli, the release of cytochrome c from mitochondria. Cytochrome c has been shown to activate the Apaf1 protein, which in turn activates the protease caspase-9 (Casp9), resulting then in cell death. In fact, the knockout of murine Apaf1 leads to embryonic lethality with a phenotype affecting several aspects of developmental apoptosis and particularly brain morphogenesis and histogenesis.^4,5,6 The Apaf1 locus maps to chromosome 12q22–q23 in humans and to chromosome 10C3-D1 in mouse.⁴

In 1997, Harris and collaborators reported that Forebrain overgrowth (fog) is an autosomal recessive mutation affecting neural tube development.⁷ This mutation was shown to map in the Apaf1 chromosomal region but the corresponding gene was uncharacterised. The resulting phenotype included mono- or bi-lateral brain bumps with subcutaneous haemorrhage covered by hair-bearing skin in adults. In addition, lumbo-sacral defects (spina bifida) were present in alternative or in association with the phenotype. Adult homozygous mouse tails often showed distal kinks or a corkscrew-like shape, with the first loop at their very base. A certain percentage of the mutants died during gestation around embryonic day 16.5 (e16.5).⁷ Recently, Honarpour et al.⁸ reported that: (a) mutant fog newborn are functionally deficient in Apaf1 protein; (b) Apaf1-transcripts are aberrantly processed in homozygous fog mutants, resulting in reduced levels of the normal Apaf1 message; and (c) Apaf1/fog double heterozygous (DH) embryos show defects consistent with those reported for fog and Apaf1 single homozygotes.

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