Control of Oocyte Reawakening by Kit

In mammals, females are born with finite numbers of oocytes stockpiled as primordial follicles. Oocytes are "reawakened" via an ovarian-intrinsic process that initiates their growth. The forkhead transcription factor Foxo3 controls reawakening downstream of PI3K-AKT signaling. However, the...

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Bibliographic Details
Published in:PLoS genetics 2016-08, Vol.12 (8), p.e1006215-e1006215
Main Authors: Saatcioglu, Hatice Duygu, Cuevas, Ileana, Castrillon, Diego H
Format: Article
Language:English
Subjects:
Age
Animals
Biology and Life Sciences
Cell Nucleus - genetics
Cellular signal transduction
Colleges & universities
Cytoplasm - genetics
Earth Sciences
Experiments
Female
Females
Forkhead Box Protein O3 - biosynthesis
Forkhead Box Protein O3 - genetics
Gene expression
Gene Expression Regulation, Developmental
Genetic aspects
Kinases
Lipids
Medicine and Health Sciences
Mice
Mice, Knockout
Mutation
Observations
Oocytes
Oocytes - growth & development
Oocytes - metabolism
Ovarian Follicle - growth & development
Ovarian Follicle - metabolism
Ovary - growth & development
Ovary - metabolism
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Primary Ovarian Insufficiency - genetics
Primary Ovarian Insufficiency - pathology
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-kit - genetics
Research and Analysis Methods
Transcription factors
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Description
Summary:In mammals, females are born with finite numbers of oocytes stockpiled as primordial follicles. Oocytes are "reawakened" via an ovarian-intrinsic process that initiates their growth. The forkhead transcription factor Foxo3 controls reawakening downstream of PI3K-AKT signaling. However, the identity of the presumptive upstream cell surface receptor controlling the PI3K-AKT-Foxo3 axis has been questioned. Here we show that the receptor tyrosine kinase Kit controls reawakening. Oocyte-specific expression of a novel constitutively-active KitD818V allele resulted in female sterility and ovarian failure due to global oocyte reawakening. To confirm this result, we engineered a novel loss-of-function allele, KitL. Kit inactivation within oocytes also led to premature ovarian failure, albeit via a contrasting phenotype. Despite normal initial complements of primordial follicles, oocytes remained dormant with arrested oocyte maturation. Foxo3 protein localization in the nucleus versus cytoplasm explained both mutant phenotypes. These genetic studies provide formal genetic proof that Kit controls oocyte reawakening, focusing future investigations into the causes of primary ovarian insufficiency and ovarian aging.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006215