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

The Kit receptor tyrosine kinase functions in hematopoiesis, 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 (P...

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Bibliographic Details
Published in:The EMBO journal 2000-03, Vol.19 (6), p.1312-1326
Main Authors: Kissel, Holger, Timokhina, Inna, Hardy, Matthew P., Rothschild, Gerson, Tajima, Youichi, Soares, Vera, Angeles, Michael, Whitlow, Scott R., Manova, Katia, Besmer, Peter
Format: Article
Language:English
Subjects:
Animals
Cell Count
Cells, Cultured
Female
Germ Cells - cytology
Hematopoiesis - genetics
Hyperplasia
Infertility - genetics
kit gene
kit protein
Kit receptor tyrosine kinase
Leydig cells
Leydig Cells - cytology
Male
Mast Cells - cytology
Mast Cells - enzymology
Meiosis - genetics
Melanocytes - cytology
Mice
Mice, Inbred Strains
oogenesis
Oogenesis - genetics
Ovarian Follicle - growth & development
Ovarian Follicle - pathology
phosphatidylinositol 3'-phosphate
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
PI 3-kinase
Pigmentation - genetics
Point Mutation - genetics
Proto-Oncogene Proteins c-kit - chemistry
Proto-Oncogene Proteins c-kit - genetics
Proto-Oncogene Proteins c-kit - metabolism
Signal Transduction
spermatogenesis
Spermatogenesis - genetics
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Summary:The Kit receptor tyrosine kinase functions in hematopoiesis, 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, KitY719F/KitY719F 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 steroido‐genesis. 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, melano‐genesis and primordial germ cell development, but is critical in spermatogenesis and oogenesis.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/19.6.1312