title: Kit signaling via PI3K promotes ovarian follicle maturation but is dispensable for primordial follicle activation.
abstract: In mammals, primordial follicles are generated early in life and remain dormant for prolonged intervals. Their growth resumes via a process known as primordial follicle activation. Recent genetic studies have demonstrated that phosphoinositide 3-kinase (PI3K) is the essential signaling pathway controlling this process throughout life, acting via Akt to regulate nucleocytoplasmic shuttling of Foxo3, which functions as a downstream molecular switch. The receptor tyrosine kinase Kit has been implicated by numerous studies as the critical upstream regulator of primordial follicle activation via PI3K/Akt. Here we present a genetic analysis of the contribution of Kit in regulating primordial follicle activation and early follicle growth, employing a knock-in mutation (Kit(Y719F)) that completely abrogates signaling via PI3K. Surprisingly, homozygous Kit(Y719F) female mice undergo primordial follicle activation and are fertile, demonstrating that Kit signaling via PI3K is dispensable for this process. However, other abnormalities were identified in Kit(Y719F) ovaries, including accelerated primordial follicle depletion and accumulation of morphologically abnormal primary/secondary follicles with persistent nuclear Foxo3 localization. These findings reveal specific roles of Kit in the maintenance of the primordial follicle reserve and in the primary to secondary follicle transition, but argue that Kit is dispensable in primordial follicle activation.
authors.affiliation: Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, 75390-9072, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: John
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Shidler
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D055879:Gene Knock-In Techniques; D051379:Mice; D009154:Mutation; D006080:Ovarian Follicle / Q000166:cytology / Q000502:physiology*; D010053:Ovary / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit