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.

Cytokine (IL16) and tyrphostin actions on ovarian primordial follicle development

“…This indicates that neither directly inhibiting JNK within the MAPK pathway nor inhibiting the focal adhesion pathway affects development at this stage and therefore neither is vital for regulating the primordial follicle transition. Several growth factors that can act in part by signaling through the MAPK pathway have been shown to regulate the primordial to primary follicle transition, including PDGF (Nilsson et al , 2006a), FGF2 (Chaves et al , 2012; Nilsson et al , 2001; Jin et al , 2005), NTF3 (Nilsson et al , 2009) and KITLD (Parrott and Skinner, 1999). Therefore, these factors likely affect follicle transition by acting through other parallel signaling pathways, rather than MAPK exclusively.…”

Ovarian Folliculogenesis

“…Additional reports demonstrated the influence of other paracrine factors on primordial follicle activation, including leukemia inhibiting factor (LIF) (Nilsson et al 2002), basic fibroblast growth factor (BFGF) (Nilsson et al 2001), keratinocyte growth factor (KGF) (Kezele et al 2005), platelet-derived growth factor (PDGF) (Nilsson et al 2006), connective tissue growth factor (CTGF) (Schindler et al 2010), and Neurotrophins (Nilsson et al 2009). Interestingly, at least part of these factors are known to activate the PI3K signaling cascade (Pangas 2012).…”

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

“…Numerous regulators that induce follicle activation have been identified including KITligand, epidermal growth factor, fibroblast growth factor 2 and 7, platelet-derived growth factor, bone morphogenetic protein 4 and 7, growth and differentiation factor 9, neurotrophin 3, brain-derived neurotrophic factor, glial-derived neurotrophic factor, insulin, interleukin 16, leukaemia inhibitory factor and gremlin (Dole et al 2008, Adhikari & Liu 2009, McLaughlin & McIver 2009, Nilsson et al 2009, Feeney et al 2014. The inhibitors of primordial activation that have been described to date include CXCL12, oestradiol, growth hormone, Hippo signalling and AMH (Adhikari & Liu 2009, McLaughlin & McIver 2009, Hsueh et al 2015.…”