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 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.
Kissel
H
H
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Timokhina
I
I
Hardy
M P
MP
Rothschild
G
G
Tajima
Y
Y
Soares
V
V
Angeles
M
M
Whitlow
S R
SR
Manova
K
K
Besmer
P
P
D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D005260:Female; D005854:Germ Cells / Q000166:cytology; D006410:Hematopoiesis / Q000235:genetics; D006965:Hyperplasia; D007246:Infertility / Q000235:genetics; D007985:Leydig Cells / Q000166:cytology; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology; D008540:Meiosis / Q000235:genetics; D008544:Melanocytes / Q000166:cytology; D051379:Mice; D008815:Mice, Inbred Strains; D009866:Oogenesis / Q000235:genetics*; D006080:Ovarian Follicle / Q000254:growth & development / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010858:Pigmentation / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013091:Spermatogenesis / Q000235:genetics*
D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit