TY - JOUR
T1 - Control of Oocyte Reawakening by Kit
AU - Saatcioglu, Hatice Duygu
AU - Cuevas, Ileana
AU - Castrillon, Diego H.
N1 - Funding Information:
We thank Aleksandar Rajkovic for the generous gift of several antibodies, and David Dankort, James Amatruda, Kent Hamra, Gina Aloisio, Mohammad Ezzati, Yuji Nakada, and Rolf Brekken for helpful discussions. We also acknowledge assistance from Dr. Bob Hammer and the UTSW Transgenic Core. We thank the University of Virginia Center for Research in Reproduction, Ligand Assay and Analysis Core for services provided under grant U54-HD028934. The authors would like to acknowledge the assistance of the UT Southwestern Live Cell Imaging Facility, a Shared Resource of the Harold C. Simmons Cancer Center, supported in part by an NCI Cancer Center Support Grant, 1P30 CA142543-01.
Publisher Copyright:
© 2016 Saatcioglu et al.
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1006215
DO - 10.1371/journal.pgen.1006215
M3 - Article
C2 - 27500836
AN - SCOPUS:84984919911
SN - 1553-7390
VL - 12
JO - PLoS Genetics
JF - PLoS Genetics
IS - 8
M1 - e1006215
ER -