Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3'-kinase is essential for male fertility.
The c-kit-encoded transmembrane tyrosine kinase receptor for stem cell factor (Kit/SCF-R) is required for normal haematopoiesis, melanogenesis and gametogenesis. However, the roles of individual Kit/SCF-R-induced signalling pathways in the control of developmental processes in the intact animal are completely unknown. To examine the function of SCF-induced phosphatidylinositol (PI) 3'-kinase activation in vivo, we employed the Cre-loxP system to mutate the codon for Tyr719, the PI 3'-kinase binding site in Kit/SCF-R, to Phe in the genome of mice by homologous recombination. Homozygous (Y719F/Y719F) mutant mice are viable. The mutation completely disrupted PI 3'-kinase binding to Kit/SCF-R and reduced SCF-induced PI 3'-kinase-dependent activation of Akt by 90%. The mutation induced a gender- and tissue-specific defect. Although there are no haematopoietic or pigmentation defects in homozygous mutant mice, males are sterile due to a block in spermatogenesis, with initially decreased proliferation and subsequent extensive apoptosis occurring at the spermatogonial stem-cell level. In contrast, female homozygotes are fully fertile. This is the first report so far demonstrating the role of an individual signalling pathway downstream of Kit/SCF-R in the intact animal. It provides the first in vivo model for male sterility caused by a discrete signalling pathway defect affecting early germ cells.
Blume-Jensen
P
P
Molecular Biology and Virology Laboratory, The Salk Institute, La Jolla, California, USA. blume@salk.edu
Jiang
G
G
Hyman
R
R
Lee
K F
KF
O'Gorman
S
S
Hunter
T
T
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D003062:Codon; D005314:Embryonic and Fetal Development; D004789:Enzyme Activation; D005091:Exons; D005260:Female; D005298:Fertility / Q000235:genetics*; D015698:Genomic Library; D006579:Heterozygote; D006720:Homozygote; D007438:Introns; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000494:pharmacology / Q000502:physiology
D003062:Codon; D019089:Stem Cell Factor; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit