Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

Abstract

Neurotrophins are growth factors that are known to have a role in promoting cell survival and differentiation. The focus of the current study is to examine the role of neurotrophins in regulating ovarian primordial follicle development. Ovaries from 4-day old rats were placed into organ culture and cultured for 10 days in the absence or presence of neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF). Treatment of ovaries with NT3 resulted in a significant (P<0.01) increase in primordial follicle development (i.e. primordial to primary follicle transition). Treatment with BDNF at high doses of 100-250 ng/ml also significantly (P<0.01) increased primordial follicle development, but NGF had no effect. Immunohistochemical studies determined that NT3 was present in granulosa cells, interstitial tissue, and in the oocytes of primordial and primary follicles. The NT3 receptor NTRK3 was present in oocytes at all stages of development. Analysis of ovaries that contain predominantly primordial follicles demonstrated the transcripts for NT3, NTRK3, NGF, and the BDNF/ neurotrophin-4 (NT4) receptor NTRK2 are expressed, while BDNF, NT4, and the NGF receptor NTRK1 are not detectable. Inhibition of the NTRK3 receptor with the tyrphostin AG 879 resulted in oocyte death and a significant (P<0.01) reduction in follicle pool size. Inhibition of the NTRK receptors with K252a slowed primordial to primary follicle transition. A microarray analysis demonstrated that a small number of genes were differentially expressed after NT3 treatment. Observations indicate that the neurotrophin NT3, acting through the NTRK3 receptor in oocytes, promotes the primordial to primary follicle transition.

Expression of neurotrophin 3 and its tropomyosin-related kinase receptor C in human preantral follicles

“…Interestingly, in early stage follicles, NT3 was more apparent in the oocyte nuclei, and TrkC was more apparent in the oocyte cytoplasm. The differences between the present results in humans and those in the rat (18) can be explained by differences between species. Moreover, mRNA transcripts for NT3 and TrkC were detected in neonatal rat ovaries (containing mainly primordial follicles) (18), and, in another study, mRNA transcripts for NT3 were detected in ovaries of human fetuses (13-21 gestational weeks) (8).…”

“…The absence of mRNA transcript staining for TrkC in fetal GCs compared with its presence in girls and women may be attributed to age-related developmental changes, as shown in the rat (18). In neonatal rat ovaries NT3 was localized in GCs and oocytes of primordial and primary follicles, although it was less prominent in oocytes of larger developing follicles (18).…”

“…In ovaries of neonatal rats, NT3 was prominent in unilaminar follicles (18); in adult rats, NT3 expression increased in developing follicles. TrkC was present in the rat at all follicular stages, and NT3 promoted the activation of rat primordial follicles.…”

“…Studies suggest that neuronal growth factors such as neurotrophins (NTs) have roles in early folliculogenesis, including growth of primordial follicles (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Neurotrophins are a family of structurally related noncovalently linked homodimer polypeptides with approximately 50% sequence identity (22,23).…”

“…Only limited information is available on the expression of NT3 or its TrkC receptor in mammalian ovaries (8,18,34,35), specifically in preantral follicles (8,18). In ovaries of neonatal rats, NT3 was prominent in unilaminar follicles (18); in adult rats, NT3 expression increased in developing follicles.…”