Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses. Export

@article{citeulike:5805939, abstract = {The Kit receptor tyrosine kinase functions in hemato- poiesis, melanogenesis and gametogenesis. Kit receptor-mediated cellular responses include proliferation, survival, adhesion, secretion and differentiation. In mast cells, Kit-mediated recruitment and activation of phosphatidylinositol 3'-kinase (PI 3-kinase) produces phosphatidylinositol 3'-phosphates, plays a critical role 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 knock-in strategy. Mutant mice have no pigment deficiency or impairment of steady-state hematopoiesis. However, gametogenesis is affected in several ways and tissue mast cell numbers are affected differentially. While primordial germ cells during embryonic development are not affected, Kit(Y719F)/Kit(Y719F) males are sterile due to a block at the premeiotic stages in spermatogenesis. Furthermore, adult males develop Leydig cell hyperplasia. The Leydig 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 for in hematopoiesis, melanogenesis and primordial germ cell development, but is critical in spermatogenesis and oogenesis.}, author = {Kissel, H. and Timokhina, I. and Hardy, M. P. and Rothschild, G. and Tajima, Y. and Soares, V. and Angeles, M. and Whitlow, S. R. and Manova, K. and Besmer, P.}, citeulike-article-id = {5805939}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/emboj/19.6.1312}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/10716931}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=10716931}, day = {15}, doi = {10.1093/emboj/19.6.1312}, issn = {0261-4189}, journal = {The EMBO journal}, keywords = {c-kit, reff, reproduction, spermatogenesis}, month = {March}, number = {6}, pages = {1312--1326}, posted-at = {2009-09-19 22:11:39}, priority = {2}, title = {Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses.}, url = {http://dx.doi.org/10.1093/emboj/19.6.1312}, volume = {19}, year = {2000} }

TY - JOUR ID - citeulike:5805939 L3 - citeulike-article-id:5805939 N2 - The Kit receptor tyrosine kinase functions in hemato- poiesis, melanogenesis and gametogenesis. Kit receptor-mediated cellular responses include proliferation, survival, adhesion, secretion and differentiation. In mast cells, Kit-mediated recruitment and activation of phosphatidylinositol 3'-kinase (PI 3-kinase) produces phosphatidylinositol 3'-phosphates, plays a critical role 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 knock-in strategy. Mutant mice have no pigment deficiency or impairment of steady-state hematopoiesis. However, gametogenesis is affected in several ways and tissue mast cell numbers are affected differentially. While primordial germ cells during embryonic development are not affected, Kit(Y719F)/Kit(Y719F) males are sterile due to a block at the premeiotic stages in spermatogenesis. Furthermore, adult males develop Leydig cell hyperplasia. The Leydig 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 for in hematopoiesis, melanogenesis and primordial germ cell development, but is critical in spermatogenesis and oogenesis. IS - 6 JF - The EMBO journal SN - 0261-4189 EP - 1326 TI - Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses. VL - 19 SP - 1312 KW - c-kit KW - reff KW - reproduction KW - spermatogenesis AU - Kissel, H AU - Timokhina, I AU - Hardy, MP AU - Rothschild, G AU - Tajima, Y AU - Soares, V AU - Angeles, M AU - Whitlow, SR AU - Manova, K AU - Besmer, P PY - 2000/03/15/ UR - http://dx.doi.org/10.1093/emboj/19.6.1312 ER -