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 fact or (Kit/SCF-R) is required for normal haema-topoiesis, melanogenesis and ga metogenesis(1-3). However, the roles of individual Kit/SCF-R-induced signal ling pathways in the control of developmental processes in the intact anima l are completely unknown. To examine the function of SCF-induced phosphatid ylinositol (PI) 3'-kinase activation in vivo, we employed the Cre-IoxP syst em(4) 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-depend ent activation of Akt by 90%. The mutation induced a gender- and tissue-spe cific defect. Although there are no haematopoietic or pigmentation defects in homozygous mutant mice, males are sterile due to a block in spermatogene sis. with initially decreased proliferation and subsequent extensive apopto sis occurring at the spermatogonial stem-cell level. In contrast, female ho mozygotes 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 caus ed by a discrete signalling pathway defect affecting early germ cells.