Point mutation in Kit receptor tyrosine kinase reveals essential roles forKit signaling in spermatogenesis and oogenesis without affecting other Kitresponses

The Kit receptor tyrosine kinase functions in hematopoiesis, melanogenesis and gametogenesis, Kit receptor-mediated cellular responses include prolife ration, survival, adhesion, secretion and differentiation. In mast cells, K it-mediated recruitment and activation of phosphatidylinositol 3'-kinase (P I 3-kinase) produces phosphatidylinositol 3'-phosphates, plays a critical r ole in mediating cell adhesion and secretion and has contributory roles in mediating cell survival and proliferation. To investigate the consequences in vivo of blocking Kit-mediated PI 3-kinase activation we have mutated the binding site for the p85 subunit of PI 3-kinase in the Kit gene, using a k nock-in strategy. Mutant mice have no pigment deficiency or impairment of s teady-state hematopoiesis, However, gametogenesis is affected in several wa ys and tissue mast cell numbers are affected differentially, While primordi al germ cells during embryonic development are not affected, Kit(Y719F)/Kit (Y719F) males are sterile due to a block at the premeiotic stages in sperma togenesis. Furthermore, adult males develop Leydig cell hyperplasia, The Le ydig cell hyperplasia implies a role for Kit in Leydig cell differentiation and/or steroidogenesis. In mutant females follicle development is impaired at the cuboidal stages resulting in reduced fertility. Also, adult mutant females develop ovarian cysts and ovarian tubular hyperplasia, Therefore, a block in Kit receptor-mediated PI 3-kinase signaling may be compensated fo r in hematopoiesis, melanogenesis and primordial germ cell development, but is critical in spermatogenesis and oogenesis.