Apaf-1 deficiency and neural tube closure defects are found in fog mice.
The forebrain overgrowth mutation (fog) was originally described as a spontaneous autosomal recessive mutation mapping to mouse chromosome 10 that produces forebrain defects, facial defects, and spina bifida. Although the fog mutant has been characterized and available to investigators for several years, the underlying mutation causing the pathology has not been known. Because 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 analysis, 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 expression levels of normal Apaf-1 mRNA. These findings are strongly suggestive of the fog mutation being a hypomorphic Apaf-1 defect and implicate neural progenitor cell death in the pathogenesis of spina bifida-a common human congenital malformation. Because a complete deficiency in Apaf-1 usually results in perinatal lethality and fog/fog mice more readily survive into adulthood, these mutants serve as a valuable model with which apoptotic cell death can be studied in vivo.
Honarpour
N
N
Departments of Molecular Genetics and Biochemistry, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas 75390-9046, USA.
Gilbert
S L
SL
Lahn
B T
BT
Wang
X
X
Herz
J
J
D000015:Abnormalities, Multiple / Q000235:genetics; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D015152:Blotting, Northern; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D005145:Face / Q000002:abnormalities; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D023421:Models, Animal; D009115:Muridae; D009436:Neural Tube Defects / Q000235:genetics*; D016548:Prosencephalon / Q000002:abnormalities; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016135:Spinal Dysraphism / Q000235:genetics; D013234:Stem Cells / Q000473:pathology
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D011506:Proteins; D012333:RNA, Messenger; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases