Abstract
BackgroundThe early stages of ovarian follicle formation—beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles—are critical in determining reproductive life span and fertility. Previously, we discovered that global knockouts of germ cell-specific transcriptional co-regulators Sohlh1, Sohlh2, Lhx8, and Nobox, cause rapid oocyte loss and ovarian failure. Also factors such as Nobox and Sohlh1 are associated with human premature ovarian failure. In this study, we developed a conditional knockout of Lhx8 to study oocyte-specific pathways in postnatal folliculogenesis.ResultsThe conditional deficiency of Lhx8 in the oocytes of primordial follicles leads to massive primordial oocyte activation, in part, by indirectly interacting with the PI3K-AKT pathway, as shown by synergistic effects on FOXO3 nucleocytoplasmic translocation and rpS6 activation. However, LHX8 does not directly regulate members of the PI3K-AKT pathway; instead, we show that LHX8 represses Lin28a expression, a known regulator of mammalian metabolism and of the AKT/mTOR pathway. LHX8 can bind to the Lin28a promoter, and the depletion of Lin28a in Lhx8-deficient oocytes partially suppresses primordial oocyte activation. Moreover, unlike the PI3K-AKT pathway, LHX8 is critical beyond primordial follicle activation, and blocks the primary to secondary follicle transition.ConclusionsOur results indicate that the LHX8-LIN28A pathway is essential in the earliest stages of primordial follicle activation, and LHX8 is an important oocyte-specific transcription factor in the ovary for regulating postnatal folliculogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0151-3) contains supplementary material, which is available to authorized users.
Highlights
The early stages of ovarian follicle formation—beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles—are critical in determining reproductive life span and fertility
Unlike the Pten pathway, we found that conditional deletion of Lhx8 from oocytes of primary follicles causes primary follicle death and depletion of the secondary/antral follicle pool
Conditional depletion of Lhx8 by Gdf9Cre causes massive primordial follicle activation We previously reported that global knockout of Lhx8 causes infertility and loss of oocytes by postnatal day 7 (PD7) [14]
Summary
The early stages of ovarian follicle formation—beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles—are critical in determining reproductive life span and fertility. We discovered that global knockouts of germ cell-specific transcriptional co-regulators Sohlh, Sohlh, Lhx, and Nobox, cause rapid oocyte loss and ovarian failure. Factors such as Nobox and Sohlh are associated with human premature ovarian failure. Germ cell cyst breakdown results in the envelopment of individual oocytes by flat granulosa cells to form primordial follicles. Primordial follicles contain small oocytes (
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