Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development.
Although communications between mammalian oocytes and their surrounding granulosa cells mediated by the Kit-Kit ligand (KL, or stem cell factor, SCF) system have been proven to be crucial for follicular development, Kit downstream signaling pathways in mammalian oocytes are largely unknown. In this study, by using ovaries and isolated oocytes from postnatal mice and rats, we demonstrated for the first time that components of the PI3 kinase pathway, the serine/threonine kinase Akt (PKB) which enhances cellular proliferation and survival, and an Akt substrate FKHRL1 which is a transcription factor that leads to apoptosis and cell cycle arrest, are expressed in mammalian oocytes. By using an in vitro oocytes culture system, we found that oocytes-derived Akt and FKHRL1 are regulated by SCF. Treatment of cultured oocytes with SCF cannot only rapidly phosphorylate and activate Akt, but also simultaneously phosphorylate and may therefore functionally suppress FKHRL1, through the action of PI3 kinase. Together with our in situ hybridization and immunohistochemistry data that Akt and FKHRL1 are mostly expressed in oocytes in primordial and primary ovaries and reports that FKHRL1 gene-deficient mice exhibited excessive activation from primordial to primary follicles as well as enlarged oocyte sizes, we suppose that in mammalian oocytes, actions of granulosa cell derived SCF on primordial to primary follicle transition and subsequent follicle development may involve activation of Akt and inhibition of FKHRL1 activities in oocytes. The role of oocyte's Akt may be to enhance follicle development and the role of oocyte's FKHRL1 may be to inhibit follicle development. We propose that the cascade from granulosa cell SCF to oocyte Kit-PI3 kinase-Akt-FKHRL1 may play an important role to regulate the growth rate of mammalian oocytes and hypothetically also the oocyte secretion of factors that may regulate the activation and early development of ovarian follicles.
Reddy
Pradeep
P
Department of Medical Biochemistry and Biophysics, Umeå University, S-901 87, Umeå, Sweden.
Shen
Lijun
L
Ren
Chong
C
Boman
Karin
K
Lundin
Eva
E
Ottander
Ulrika
U
Lindgren
Peter
P
Liu
Yi-Xun
YX
Sun
Qing-Yuan
QY
Liu
Kui
K
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006107:Granulosa Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D009865:Oocytes / Q000254:growth & development / Q000502:physiology*; D006080:Ovarian Follicle / Q000254:growth & development / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000502:physiology*
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D019089:Stem Cell Factor; C499515:FOXO3 protein, rat; C474033:FoxO3 protein, mouse