Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence

Abstract

Reproductive competence in mammals depends on the projection of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the hypothalamic–pituitary–gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle.

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Hypothalamic tanycytes are important players in the neuroendocrine system (Caruso et al, 2010;Mullier et al, 2010;Parkash et al, 2015;Rodríguez et al, 2005), they contribute to the regulation of GnRH release, the maintenance of energy homeostasis and the control of body weight (Argente-Arizon et al, 2015;Bolborea and Dale, 2013;Garcia-Segura et al, 2008;Langlet, 2014;Ojeda et al, 2008;Prevot et al, 2010).…”

Shaping the Reproductive System: Role of Semaphorins in Gonadotropin-Releasing Hormone Development and Function

“…However, the molecular cues responsible for these dynamic morphological changes have not been elucidated so far. We have recently demonstrated a novel mechanism for this plasticity in the ME of adult female rodents, where tanycytes express Sema7A and this expression varies as a function of the hormonal state of the animal during the estrous cycle, being maximal at the onset of the diestrous phase [139]. We hypothesize that Sema7A released by hypothalamic tanycytes cyclically induces GnRH neurons to retract their terminals from the pericapillary space through PlexinC1 signaling and concomitantly promotes tanycytic end feet expansion via β 1 -integrin activation, making the pericapillary space inaccessible to GnRH nerve terminals (fig.…”

“…Interestingly, β 1 -integrin deletion in adult tanycytes leads to an alteration of the estrous cycle with a predominance of estrous stages with elevated circulating levels of LH [139]. …”

“…During diestrus, when progesterone secretion reaches peak values, while estrogen levels are low, progesterone stimulates Sema7A expression in tanycytes. Through a bifunctional mechanism of action, Sema7A induces, through β 1 -integrin activation, the expansion of tanycytic end feet, which ensheathe GnRH nerve terminals, and via PlexinC1, the retraction of GnRH nerve endings, thus preventing the free diffusion of the neurohormone into the pericapillary space [139]. …”

An updated view of hypothalamic–vascular–pituitary unit function and plasticity

“…2) The cellular conformation changes with fluctuating oestrogen profiles throughout the oestrous cycle. For example, in rats, semaphorin-7a-dependent structural remodelling of tanycytes occurs during the preovulatory surge, resulting in release of the engulfed axons and direct access of GnRH nerve terminals to the portal vasculature 60 (FIG. 2).…”