The ovulatory and luteotropic actions of the male-derived beta-nerve growth factor in South American camelids

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The neurotrophin beta-nerve growth factor (β-NGF) has a potent LH-releasing effect and is the main trigger for ovulation in camelids. The β-NGF exerts luteotropic effects in camelids not only via enhanced LH release but also by acting at the ovary, where stimulates steroidogenic enzyme expression in luteal cells as well as vascularization of the corpora lutea. The mechanism of ovulation of β-NGF implicates central neuroendocrine systems that result in GnRH release. Also, recent works have shown pro-luteotropic effects of β-NGF in cattle. Thus, β-NGF might be a potential biotechnology tool to enhance fertility in farm production systems. Induced ovulation is considered an evolutionary reproductive trait developed by some species to achieve fertilization success (Bakker and Baum, 2000). This ovulation mechanism is mostly observed in animal species exhibiting low population densities or inhabiting highly seasonal environments, and it is intimately linked to copulation (Bakker and Baum, 2000). Tactile, visual, and olfactory stimuli occurring during mating behavior have been classically linked to eliciting or facilitating ovulation in induced ovulators. Since its early definition, the mechanical stimulation of the vagina and cervix during penile intromission that stimulates afferent sensory inputs has been ascribed to the main factor triggering a neuroendocrine reflex responsible for the preovulatory luteinizing hormone (LH) surge and subsequently ovulation (Kauffman and Rissman, 2006). However, not much consideration has been given to the chemical or hormonal effect that semen can have on triggering the release of the oocyte. The notion that the male could signal and influence the female reproductive physiology to improve the conditions for pregnancy success through semen deposition in the female tract is a notion just recently considered (Robertson, 2007). In fact, several studies have demonstrated that molecules present in the seminal fluid of different species can affect fertilization, early embryo survival, endometrial receptivity, and finally pregnancy outcome (Robertson, 2007). Recently, it has been proposed to extend further the concept of pheromones, based on the observations made in camelids, to include along with the classic air-borne chemical signals a separate class of seminal molecules that act on the female reproductive tract (Robertson and Martin, 2022). Seminal plasma is the largest portion of an ejaculate containing sugars, salts, lipids, proteins, hormones, antimicrobial molecules, and others acting as immunity suppressors. Nowadays, it is clear that apart from the role of several of these molecules on sperm physiology, they have a role in chemical communication between males and females that surpass mating itself (Robertson, 2007; Schjenken and Robertson, 2020). In this regard, findings reported during the last 30 yr provide robust evidence of the presence of an ovulation-inducing factor (OIF) in the seminal plasma of old (Bactrian and Dromedary camels) and new (llamas and alpacas; Figure 1) world camelids, which unequivocally support a pivotal role of the male on the control of female reproduction via seminal plasma signals in camelids. Domestic South American camelids. Llamas (upper panel) and alpacas (low panel) are domestic species native to the Andean region of Peru, Bolivia, and northern Chile and Argentina. Small herds can be easily kept for different purposes in lowlands as illustrated in the pictures, which are located in Southern Chile. Early South American studies classified female llamas and alpacas as induced ovulators based on experimental designs that included different mating variations (San-Martin et al., 1968; Fernandez-Baca et al., 1970). These studies established the classic notion that the mechanical stimulation occurring during copulation was required to induce the preovulatory LH surge and subsequent ovulation. However, as mentioned, later studies elucidated and provided depth insights into the mechanism of induced ovulation in domestic South American camelids, which is driven by a protein factor present in the seminal plasma rather than by physical stimulation of the female genital tract and subsequent nerve transduction (Ratto et al., 2012). Besides the effect on the induction of ovulation in llamas and alpacas that occurs shortly after systemic protein administration, this ovulation-inducing factor also enhances the development and function of the corpus luteum (Adams et al., 2005; Silva et al., 2014; Ulloa-Leal et al., 2014), a potential strategy to stimulate early embryo development and implantation. The present review aims to condense most of our current understanding regarding the major female reproductive effects of the OIF—also known as beta-nerve growth factor (β-NGF)—that is present in the male llama and alpaca seminal plasma, as well as its possible mechanisms of actions in the brain which still awaits to be elucidated. A potential use of β-NGF in the light of recent evidence of its effect in cattle is also reviewed. In the ‘80s, the pioneering work of Chinese researchers (Chen et al., 1983) brought to our attention the fact that a high rate of ovulations was induced after intravaginal deposition of semen in Bactrian camels, an induced ovulation species. After two decades of intense work, the research conducted in Bactrian camels has led to the following findings: 1) rather than the mechanical stimulation of copulation, a protein present in the seminal plasma is responsible for triggering ovulation in this species (Chen et al., 1983, 1985); 2) after systemic or intrauterine administration of the seminal factor, a rapid preovulatory LH surge is induced (Xu et al., 1985); 3) the protein factor is chemically different from other ovulatory molecules (gonadotropin-releasing hormone [GnRH], LH, Human chorionic gonadotropin [hCG], equine chorionic gonadotropin [eCG], and prostaglandin F2alpha [PGF2α] ; Pan et al., 2001); and 4) this factor is transported via the bloodstream to upper central structures that control reproduction (Zhao et al., 1990). However, the complete identification of the seminal factor in Bactrian camels could not be accomplished, so generically it was called OIF. Two decades after the Bactrian camel studies, Adams et al. (2005) reported the existence of an OIF in the seminal plasma of llamas and alpacas, demonstrating that the administration of a single intramuscular dose of seminal plasma can lead to high rates of ovulation and also an enhanced preovulatory LH surge that, in turn, determined a larger secretion of progesterone from the resulting corpus luteum, and so providing the first evidence of a luteotropic effect of OIF. Since these early studies, llamas and alpacas have constituted a useful animal model to study the OIF using either homologous or heterologous seminal plasma (Adams et al., 2005; Ratto et al., 2005, 2006), seminal fractions (Ratto et al., 2010, 2011), or purified OIF (Silva et al., 2011; Tanco et al., 2011; Ulloa-Leal et al., 2014) given by intramuscular, intravenous, or intrauterine routes. In the last decade, this factor has been biochemical and functionally characterized in llamas and alpacas as the neurotrophin β-NGF (Ratto et al., 2011, 2012, Kershaw-Young et al., 2012), a molecule exhibiting a potent ovulatory effect in both alpacas and llamas, and also a significant luteotropic effect in llamas (Adams et al., 2005; Silva et al., 2014; Ulloa-Leal et al., 2014). Nevertheless, a similar effect has not been confirmed in alpacas (Kershaw-Young et al., 2012; Stuart et al., 2015). Subsequent studies also reported its presence in the seminal plasma of other species, including dromedary camels (Druart et al., 2013; Kumar et al., 2013). In a cleverly designed experiment, Berland et al. (2016) confirmed that intrauterine administration of seminal plasma, but not penile intromission, is sufficient to elicit the LH surge and ovulation in this species: female llamas mate

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