Leukemia inhibitory factor (LIF) promotes the primordial to primary follicle transition in rat ovaries.

In a sexually mature female, primordial follicles continuously leave the arrested pool and undergo the primordial to primary follicle transition. The oocytes increase in size and the surrounding squamous pre-granulosa cells become cuboidal and proliferate to form a layer of cuboidal cells around the growing oocyte. This development of the primordial follicle commits the follicle to undergo the process of folliculogenesis. When the available pool of primordial follicles is depleted reproductive function ceases and humans enter menopause. The current study examines whether leukemia inhibitory factor (LIF) promotes the primordial to primary follicle transition that initiates follicular development. Ovaries from 4 day-old rats were cultured in the absence or presence of LIF or neutralizing antibody to LIF. LIF treatment increased the proportion of follicles that initiated the primordial to primary follicle transition to 59%, compared to 45% in untreated cultured ovaries. The ability of LIF to induce primordial follicle development was enhanced to greater than 75% by the presence of insulin in the culture medium. Anti-LIF neutralizing antibody reduced the proportion of spontaneous developing primordial follicles. Immunocytochemical studies demonstrated higher levels of LIF protein in the granulosa and surrounding somatic cells of primordial and primary follicles compared to the oocyte. In contrast, later pre-antral and antral stage follicles showed LIF expression primarily in the oocyte. In granulosa and theca cell cultures LIF had no effect on cell proliferation. However, LIF treatment did increase expression of Kit ligand (KL) mRNA in cultured granulosa cells. KL has been shown to promote ovarian cell growth and induce primordial follicle development. LIF induction of KL expression may be involved in the actions of LIF to promote primordial to primary follicle transition. In summary, LIF treatment increased the primordial to primary follicle transition in cultured ovaries and LIF may interact with KL to promote primordial follicle development.