TrkB receptors are required for follicular growth and oocyte survival in the mammalian ovary

Abstract

Although it is well established that both follicular assembly and the initiation of follicle growth in the mammalian ovary occur independently of pituitary hormone support, the factors controlling these processes remain poorly understood. We now report that neurotrophins (NTs) signaling via TrkB receptors are required for the growth of newly formed follicles. Both neurotrophin-4/5 (NT-4) and brain-derived neurotrophic factor (BDNF), the preferred TrkB ligands, are expressed in the infantile mouse ovary. Initially, they are present in oocytes, but this site of expression switches to granulosa cells after the newly assembled primordial follicles develop into growing primary follicles. Full-length kinase domain-containing TrkB receptors are expressed at low and seemingly unchanging levels in the oocytes and granulosa cells of both primordial and growing follicles. In contrast, a truncated TrkB isoform lacking the intracellular domain of the receptor is selectively expressed in oocytes, where it is targeted to the cell membrane as primary follicles initiate growth. Using gene-targeted mice lacking all TrkB isoforms, we show that the ovaries of these mice or those lacking both NT-4 and BDNF suffer a stage-selective deficiency in early follicular development that compromises the ability of follicles to grow beyond the primary stage. Proliferation of granulosa cells-required for this transition-and expression of FSH receptors (FSHR), which reflects the degree of biochemical differentiation of growing follicles, are reduced in trkB-null mice. Ovaries from these animals grafted under the kidney capsule of wild-type mice fail to sustain follicular growth and show a striking loss of follicular organization, preceded by massive oocyte death. These results indicate that TrkB receptors are required for the early growth of ovarian follicles and that they exert this function by primarily supporting oocyte development as well as providing granulosa cells with a proliferative signal that requires oocyte-somatic cell bidirectional communication. The predominance of truncated TrkB receptors in oocytes and their developmental pattern of subcellular expression suggest that a significant number of NT-4/BDNF actions in the developing mammalian ovary are mediated by these receptors.

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

“…The NTRK2 receptor probably has a role in larger developing follicles. In mice that are genetically lacking either NTRK2 expression or both BDNF and NT4 expression, primordial to primary follicle transition occurs, but growth of follicles beyond the primary stage is compromised (Paredes et al 2004). This supports the idea that BDNF/NTRK2 signaling is not important for primordial follicle transition in rodents.…”

The promoter of the oocyte-specific gene, Gdf9, is active in population of cultured mouse embryonic stem cells with an oocyte-like phenotype

“…LIF has been widely studied as a media additive important for the maintenance of ES cells in a self-renewing, undifferentiated state [21][22][23][24]. However, based on several reports demonstrating the importance of LIF not only in the survival and self-renewal of PGCs [25][26][27]44], but also in the maturation of oocytes and ovarian follicles [26,28,31,45], we decided to study its role in the formation of germ cells from ES cells in vitro. We found that LIF, when added to the media of ES cells differentiating in the absence of a MEF monolayer, significantly increased not only the number of eGFP-positive oocyte-like cells, but also the expression of oocyte specific genes in vitro.…”

“…BDNF is a member of the neurotrophin family of proteins that are widely expressed in the central nervous system and important for neuronal function [30]. Several studies have shown that BDNF plays a role in non-neuronal tissues, including in the ovary, where it was found to be essential for the development of early follicles and for oocyte maturation [30][31][32]. Members of the TGFβ superfamily have also been shown to play important roles in ovarian development starting with the specification of primordial germ cells by the bone morphogenetic proteins through to the recruitment of primordial follicles by anti-Mullerian hormone and, finally, their transformation into preantral and antral follicles in response to activin and TGFβ [33−35].…”

The roles of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and nerve growth factor during the final stage of folliculogenesis: a focus on oocyte maturation

“…The effects of neurotrophins on developing ovarian follicles have been investigated in the context of follicular survival, assembly and growth (Paredes et al 2004, Dole et al 2008, Dissen et al 2009, Kerr et al 2009, Dorfman et al 2011 and have been reviewed elsewhere (Ojeda et al 2000). However, studies investigating their role in antral follicles during the final stage of folliculogenesis, marked by oocyte maturation and the resumption of meiosis, which is concomitant with extrusion of the first polar body, as well as developmental competence of the early embryo, have not been reviewed in detail.…”