Zygote 4 (November), pp 309-312. Copyright © 1996 Cambridge University Press Printed in Great Britain Participation of nerve growth factor in the regulation of ovarian function Gregory A. Dissen, Artur Mayerhofer and Sergio R. Ojeda Division of Neuroscience, Oregon Regional Primate Research Center/Oregon Health Sciences University, Portland, Oregon, USA Nerve growth factor (NGF) belongs to a family of related target-derived proteins required for the sur- vival and development of discrete neuronal popula- tions in the central and peripheral nervous systems (Levi-Montalcini, 1987; Snider, 1994). Although initial observations led to the conclusion that the biological actions of neurotrophins are restricted to the nervous system (Thoenen, 1991; Raffioni et al., 1993), new evidence suggests that they, and in particular NGF, can also affect non-neuronal cells. NGF is recognised by two different membrane-spanning receptor mole- cules: one displaying rapid dissociation kinetics, known as low-affinity NGF receptor or p75 NTR , and another with a slow dissociation rate, known as trkA (Barbacid et al, 1991; Meakin and Shooter, 1992). Although p75 NTR binds all other neurotrophins (NTs), including brain-derived neurotrophic factor (BDNF), NT-3 and NT-4/5, with similar low affinity (Thoenen, 1991; Meakin & Shooter, 1992), the trkA receptor binds NGF preferentially and with high affinity (Kaplan et al, 1991a; Klein et al, 1991). The p75 NTR potentiates the effects of trkA activation (Benedetti et al, 1993; Hant- zopoulos et al., 1994), but also has an independent role in apoptosis, as the receptor has been shown to activate expression of the nuclear transcription factor NF-KB (Carter et al, 1996), a downstream gene in- volved in modulating cell death signals conveyed to the cell by cytokines produced in the immune system. In contrast, trkA, which is endowed with a tyrosine kinase domain similar to that of other receptor tyro- sine kinases (Martin-Zanca et al, 1989; Kaplan et al, 1991b), has been shown to mediate the biological effects of NGF via activation of a signalling pathway similar to that activated by mitogenic receptor tyrosine kinases (Szeberenyi & Erhardt, 1994). Our laboratory has been examining, first, the expression of neurotro- phins and their receptors in the ovary and, second, the possible roles that these molecules may play in ovarian function. All correspondence to: G.A. Dissen, Division of Neuro- science, Oregon Regional Primate Research Center/Oregon Health Sciences University, 505 N.W. 185th Avenue, Port- land, OR 97006-3499, USA. Possible involvement of NGF in ovulation Mammalian ovulation resembles an inflammatory re- action, but rather than being started by injury, it is initiated by hormonal stimulation. The inflammatory- like changes that precede ovulation result in the rupture of healthy antral follicles to allow release of the oocyte for fertilisation. Factors known to be involved in inflammation include interleukins, prostaglandins, vasoactive agents and proteases; all of them have been found to be produced by follicular cells during the periovulatory period (Espey & Lipner, 1994). We have found that both trkA and NGF gene expression increase following the gonadotropin surge and preceding ovu- latory rupture of the follicle (Dissen et al, 1996a). The remarkable fugacious nature and magnitude of the NGFI trkA gene activation suggests that NGF-initiated frfcA-mediated responses are integral components of ovulation; virtually no trkA mRNA can be detected either shortly before the preovulatory LH surge (morning of pro-oestrus) or a few hours after ovulation, i.e. on the morning of the first oestrus, whereas more than a 100-fold increase in mRNA levels occurs shortly after the LH surge. Both NGF and trkA are produced by thecal cells of large antral follicles and interstitial cells, as shown by immunohistochemistry and hybridi- sation histochemistry (Dissen et al, 1996a). The activa- tion of the trkA gene in non-neural cells of the ovarian follicle at a time when the follicle is becoming bio- chemically and cytologically differentiated into a new structure, the corpus luteum, suggests that ligand- mediated activation of trkA receptors contributes to these acute differentiating events. Supporting this view is the finding that both immunoneutralisation of NGF actions and pharmacological blockade of trk receptor- mediated intracellular signalling with K-252a lead to inhibition of ovulation (Dissen et al., 1996a). A close relationship between ovulation and inflam- mation is further suggested by the effectiveness of interleukin-ip (IL-Ifj) in increasing NGF and trkA mRNA levels in ovarian cells and the ability of both NGF antibodies and K-252a to reduce the increase in prostaglandin E 2 (PGE 2 ) elicited by this cytokine. These results suggest that NGF may mediate at least