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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.

Pubmed ID: 10716931


  • Kissel H
  • Timokhina I
  • Hardy MP
  • Rothschild G
  • Tajima Y
  • Soares V
  • Angeles M
  • Whitlow SR
  • Manova K
  • Besmer P


The EMBO journal

Publication Data

March 15, 2000

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL/DK55748
  • Agency: NCI NIH HHS, Id: R37 CA32926

Mesh Terms

  • Animals
  • Cell Count
  • Cells, Cultured
  • Female
  • Germ Cells
  • Hematopoiesis
  • Hyperplasia
  • Infertility
  • Leydig Cells
  • Male
  • Mast Cells
  • Meiosis
  • Melanocytes
  • Mice
  • Mice, Inbred Strains
  • Oogenesis
  • Ovarian Follicle
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Pigmentation
  • Point Mutation
  • Proto-Oncogene Proteins c-kit
  • Signal Transduction
  • Spermatogenesis