Deficiency of Trp53 rescues the male fertility defects of Kit(W-v) mice but has no effect on the survival of melanocytes and mast cells.
Mutations of the receptor tyrosine kinase, Kit, or its ligand, mast growth factor (Mgf), affect three unrelated cell populations: melanocytes, germ cells, and mast cells. Kit signaling is required initially to prevent cell death in these lineages both in vitro and in vivo. Mgf appears to play a role in the survival of some hematopoietic cells in vitro by modulating the activity of p53. Signaling by Mgf inhibits p53-induced apoptosis of erythroleukemia cell lines and suppresses p53-dependent radiation-induced apoptosis of bone marrow cells. We tested the hypothesis that cell survival in Kit mutant mice would be enhanced by p53 deficiency in vivo. Double-mutant mice, which have greatly reduced Kit receptor tyrosine kinase activity and also lack Trp53, were generated and the affected cell lineages examined. Mast cell, melanoblast, and melanocyte survival in the double Kit(W-v/W-v):Trp53(-/-) mutants was not increased compared to the single Kit(W-v/W-v):Trp53(+/+) mutants. However, double-mutant males showed an increase in sperm viability and could father litters, in contrast to their homozygous Kit mutant, wild-type p53 littermates. This germ cell rescue appears to be male specific, as female ovaries were similar in mice homozygous for the Kit mutant allele with or without p53. We conclude that defective Kit signaling in vivo results in apoptosis by a p53-independent pathway in melanocyte and mast cell lineages but that in male germ cells apoptosis in the absence of Kit is p53-dependent.
Jordan
S A
SA
MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
Speed
R M
RM
Bernex
F
F
Jackson
I J
IJ
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D005260:Female; D016158:Genes, p53; D005838:Genotype; D006720:Homozygote; D007248:Infertility, Male / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008407:Mast Cells / Q000166:cytology*; D008544:Melanocytes / Q000166:cytology*; D051379:Mice; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010053:Ovary / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D019089:Stem Cell Factor / Q000502:physiology; D013737:Testis / Q000166:cytology / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D019089:Stem Cell Factor; D016159:Tumor Suppressor Protein p53; D019009:Proto-Oncogene Proteins c-kit