Abstract
In females, germ cells are maintained in ovarian structures called primordial follicles. The number of primordial follicles in the ovarian reserve is a critical determinant of the length of the fertile lifespan. Despite this significance, knowledge of the precise physiological mechanisms that regulate primordial follicle number is lacking. In this study we show that a wave of primordial follicle depletion occurs during the transition to adulthood in mice. We demonstrate that this sudden and dramatic loss of primordial follicles is hormonally triggered and identify the pro-apoptotic BH3-only protein, BCL-2 modifying factor (BMF), as essential for this process, implicating the intrinsic apoptotic pathway as a key mechanism. The elimination of primordial follicles during puberty is not only a striking developmental event, it is also physiologically important because it ultimately reduces the availability of primordial follicles and determines the duration of fertility. Collectively, these findings show that puberty is a critical developmental window for the regulation of the size of ovarian reserve, impacting on female fertility and reproductive longevity.
Highlights
A number of studies have documented the numeric decline in primordial follicles after birth.[1,5,6,7,8,9,10] One such study in mice showed that the initial ovarian reserve of primordial follicles is depleted by more than two-thirds between postnatal day (PN) 6 and 45.8 After PN45, when mice are considered sexually mature, primordial follicles were lost from the ovarian reserve much more gradually.[8]
We recently reported that ovaries from juvenile (PN20) Bmf−/− and wild-type (WT) mice had similar numbers of primordial follicles, but while primordial follicle numbers fell considerably in ovaries WT mice by PN100, significantly fewer primordial follicles were lost in the BCL-2 modifying factor (BMF)-deficient females during this period.[5]
We report the following major findings: (1) we show that a wave of primordial follicle loss occurs during puberty in mice, (2) we use a genetic mouse model to demonstrate that apoptosis is required for the pubertal wave of primordial follicle loss and to identify BMF as the key apoptotic protein involved, and (3) we use mouse models of early gonadotropin exposure and puberty suppression to show that primordial follicle loss is actively triggered by gonadotropins
Summary
A number of studies have documented the numeric decline in primordial follicles after birth.[1,5,6,7,8,9,10] One such study in mice showed that the initial ovarian reserve of primordial follicles is depleted by more than two-thirds between postnatal day (PN) 6 and 45.8 After PN45, when mice are considered sexually mature, primordial follicles were lost from the ovarian reserve much more gradually.[8]. We report the following major findings: (1) we show that a wave of primordial follicle loss occurs during puberty in mice, (2) we use a genetic mouse model to demonstrate that apoptosis is required for the pubertal wave of primordial follicle loss and to identify BMF as the key apoptotic protein involved, and (3) we use mouse models of early gonadotropin exposure and puberty suppression to show that primordial follicle loss is actively triggered by gonadotropins. The latter finding reveals a novel and unexpected role for gonadotropins during puberty
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