Loss of inhibin alpha uncouples oocyte-granulosa cell dynamics and disrupts postnatal folliculogenesis

Abstract

Targeted disruption of the inhibin α gene (Inha−/−) in mice results in an ovarian phenotype of granulosa cell tumors that renders the animals infertile. Little is known about the reproductive defects prior to tumor development. Here, we report novel data on early follicle dynamics in Inha−/− mice, which demonstrate that inhibin α has important consequences upon follicle development. Morphological changes in both germ and somatic cells were evident in postnatal day 12 ovaries, with Inha−/− mice exhibiting numerous multilayered follicles that were far more advanced than those observed in age-matched controls. These changes were accompanied by alterations in follicle dynamics such that Inha−/− ovaries had fewer follicles in the resting pool and more committed in the growth phase. Absence of inhibin α resulted in advanced follicular maturation as marked by premature loss of anti-Müllerian hormone (AMH) in secondary follicles. Additionally, gene expression analysis revealed changes in factors known to be vital for oocyte and follicle development. Together, these data provide key evidence to suggest that regulation of the inhibin/activin system is essential for early folliculogenesis in the prepubertal mouse ovary.

Coupled Somatic Cell Kinetics and Germ Cell Growth: Multiscale Model-Based Insight on Ovarian Follicular Development

“…In our simulations, this phenotype was mimicked by decreasing the κ 1 value without changing the value of λ 1 , in agreement with the low expression of kitlg observed in these transgenic ovaries [34]. From the definition of the different domains delimited by the values of the (λ 1 , κ 1 ) couple (see Figure 3.6), both a decrease in the ratio κ 1 /λ 1 from its initial value in wild-type animals, or a high increase in the λ 1 value, could also explain the ovarian phenotype of the inhibin-deficient mice.…”

“…From the definition of the different domains delimited by the values of the (λ 1 , κ 1 ) couple (see Figure 3.6), both a decrease in the ratio κ 1 /λ 1 from its initial value in wild-type animals, or a high increase in the λ 1 value, could also explain the ovarian phenotype of the inhibin-deficient mice. However, follicular growth appears to be enhanced in the ovaries of these transgenic mice [34], suggesting that an increase in the value of λ 1 is unlikely. In humans, an imbalance between the dynamics of oocyte growth and granulosa cell proliferation has been reported in the small growing follicles of polycystic ovaries, and intrinsic abnormality of early follicle development in the ovary has been proposed to be key to their pathogenesis [40].…”

“…Altered relationships between oocyte growth and granulosa cell proliferation have been reported in other mammalian species, in experimental or pathological conditions. For example, the inhibin-deficient mice resulting from targeted disruption of the Inha (inhibin α) gene are characterized by very large multilayered preantral follicles containing small oocytes, and abnormal ovarian expression of gdf9, bmp15 and kitlg [34].…”

The ovary: basic biology and clinical implications

“…In addition, Inha -/-female mice are infertile prior to gross tumor development, as determined by their inability to ovulate and the lack of late-stage follicle development (83). Inhibin does not appear to be essential for embryonic oocyte development, germ cell syncytia breakdown, or primordial follicle formation because the ovaries of newborn Inha -/-mice have normal numbers of oocytes and develop equivalent numbers of primordial follicles as the ovaries of wild-type mice in the three days after birth (84). However, marked changes in the ovaries of Inha -/-and wild-type mice occur during the period of secondary follicle to early antral follicle development (Figure 2), which occurs after 6 days of age.…”

“…The lack of oocyte growth is likely related to decreased expression of Kitl, as the gene encoding the receptor for the Kitl gene product is expressed in oocytes and is critical for oocyte growth and development (85). Both GDF9 and activin are known to decrease expression of Kitl (19,86), and both Gdf9 and the genes encoding inhibin βA and βB subunits are overexpressed in Inha -/-ovaries (84). Additionally, there is loss of oocyte-expressed Bmp15 and granulosa cell-expressed anti-Müllerian hormone (Amh), two growth factors that also modulate follicle growth.…”