Origin and Ontogeny of Mammalian Ovarian Neurons

Abstract

Mammalian ovaries contain sympathetic neurons expressing the low affinity neurotropin receptor (p75NTR). To date neither the role these neurons might play in ovarian physiology nor their embryological origin is known. Immunohistochemistry was used to detect postnatal changes in distribution and number of both p75NTR-positive and tyrosine hydroxylase-positive neurons in rhesus monkey ovaries. Pig fetuses were used to map the pathway of ovarian neuronal migration during embryonic development. Antiserum to p75NTR revealed the presence of isolated neurons and neurons clustered into ganglia in 2-month-old monkey ovaries. After 8 months, the neurons exhibited well-developed processes, and other than being more extensively interlaced, the localization and morphology did not change after 2 yr of age. Total number of p75NTR-positive neurons present decreased gradually between 2 months and 12 yr of age and declined markedly with reproductive aging. Conversely, the subpopulation of neurons immunoreactive to anti-tyrosine hydroxylase increased significantly at puberty and then declined with the loss of reproductive capacity. By d 21 of fetal life in the pig, p75NTR neurons had migrated medially from the neural crest to form the paraaortic autonomic ganglia. Some neurons migrated ventrally from the ganglia and then continued ventrolaterally to enter the genital ridge. By d 27, neurons had entered the developing ovary, and by d 35, the migration was complete with neurons demonstrating immunoreactivity to NeuN, a neuron-specific marker. Results demonstrate that p75NTR-expressing ovarian neurons originate from the neural crest and that a catecholaminergic subset is associated with pubertal maturation of the ovary and subsequent reproductive function.

Functional Development of the Ovarian Noradrenergic Innervation

“…This conclusion is in keeping with findings in rhesus monkeys showing that both the density and composition of the sympathetic ovarian innervation, in addition to the number of intrinsic catecholaminergic neurons present in the ovary of this species, reach a maximum near the time of puberty (16,18). It would not be unreasonable to expect that similar developmental changes in sympathetic input to the ovary occur in humans because the adult human ovary not only contains TH-positive nerve terminals but also responds to depolarization with incorporation and release of NE (37).…”

“…Total incorporation of 3 H-NE into ovarian tissue increased moderately during the neonatal-infantile period (d [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and then abruptly during the second half of juvenile development (d 26 -30), remaining elevated at puberty (d [31][32][33][34][35], and after the first ovulation (d 40) (Fig. 1A).…”

“…The presence of sympathetic nerves in the mammalian ovary before birth (15,16) and the ability of the neonatal ovary to respond in vitro to ␤-adrenergic stimulation with cAMP production and synthesis of FSH receptors led to the suggestion that neural activity might be an important factor in the regulation of follicular development before the ovary acquires responsiveness to gonadotropins (17). According to this concept, ovarian nerves may act via neurotransmitters coupled to the cAMP-generating system to influence the differentiation process by which newly formed primary follicles acquire FSH receptors and responsiveness to FSH.…”

Building the mammalian testis: origins, differentiation, and assembly of the component cell populations

“…It is assumed that these are extrinsic nerves entering the gonad by innervation, and the existence of intrinsic neurons in the fetal testis has not been clearly established. Nevertheless, intrinsic neurons have been identified in postnatal testes of primates (Mayerhofer et al 1996a;Mayerhofer et al 1999;Frungieri et al 2000) and also in fetal ovaries of both humans and pigs (Anesetti et al 2001;Dees et al 2006). In rodent ovaries, there appear to be few or no intrinsic neurons (D'Albora and Barcia 1996; D' Albora et al 2000).…”

Androgen Receptor (AR) Physiological Roles in Male and Female Reproductive Systems: Lessons Learned from AR-Knockout Mice Lacking AR in Selective Cells1

“…In contrast, the results of Sen and Hammes [9] indicated that loss of AR function in granulosa cells is sufficient to effect dysregulation of the estrous cycle, suggesting possible generation of a negative modulator of cycle regulation. Ovaries of various mammalian species are subjected to sympathetic innervation to form an intrinsic neural network, which changes with age and declines with reproduction aging [162]. If the putative ovarian negative regulator generated by the loss of granulosa AR acts through the ovarian neural reflex, such an effect would not be observed in Wt hosts transplanted with mutant AR ÀEX3 ovaries.…”