SynCAM1, a Synaptic Adhesion Molecule, Is Expressed in Astrocytes and Contributes to erbB4 Receptor-Mediated Control of Female Sexual Development

Abstract

Female sexual maturation requires erythroblastosis B (erbB)4 signaling in hypothalamic astrocytes; however, the mechanisms by which erbB4 contributes to this process are incompletely understood. Here we show that SynCAM1, a synaptic adhesion molecule with signaling capabilities, is not only expressed highly in neurons, but also in hypothalamic astrocytes and is functionally associated with erbB4 receptor activity. Whereas SynCAM1 expression is diminished in astrocytes with impaired erbB4 signaling, ligand-dependent activation of astroglial erbB4 receptors results in rapid association of erbB4 with SynCAM1 and activation of SynCAM1 gene transcription. To determine whether astrocytic SynCAM1-dependent intracellular signaling is required for normal female reproductive function, we generated transgenic mice that express in an astrocyte-specific manner a dominant-negative form of SynCAM1 lacking the intracellular domain. The mutant protein was correctly targeted to the cell membrane and was functionally viable as shown by its ability to block intracellular calcium/calmodulin-dependent serine protein kinase redistribution, a major SynCAM1-mediated event. Dominant-negativeSynCAM1 female mice had a delayed onset of puberty, disrupted estrous cyclicity, and reduced fecundity. These deficits were associated with a reduced capacity of neuregulin-dependent erbB4 receptor activation to elicit prostaglandin E2 release from astrocytes and GnRH release from the hypothalamus. We conclude that one of the mechanisms underlying erbB4 receptormediated facilitation of glial-neuronal interactions in the neuroendocrine brain involves Syn-CAM1-dependent signaling and that this interaction is required for normal female reproductive function. (Endocrinology 152: 2364 -2376, 2011) T he erythroblastosis (erbB) family of tyrosine kinase receptors and their respective ligands regulate a variety of developmental processes and mature cellular functions in different tissues (1). In the nervous system, erbB receptors not only contribute to the control of neurogenesis and transsynaptic communication but also play a central role in the regulation of glial biology and development (2, 3). In the case of astrocytes, it was recently shown that neuregulin (NRG)-1-dependent activation of erbB receptors regulates the timing of astrogenesis in brain (4). Yet little is known about the contribution of NRG-erbB signaling to other aspects of astrocyte biology.

Role of Glia in the Regulation of Gonadotropin-Releasing Hormone Neuronal Activity and Secretion

“…The ligand-induced activation of erbB4 receptors promotes the physical interaction of erbB4-SynCAM1 through their intracellular domains and stimulates the adhesive behavior of SynCAM1. SynCAM1 is in turn necessary for neuregulin-dependent erbB4 activation to elicit PGE2 release from astrocytes and GnRH release from nerve terminals [66,68]. Hypothalamic astrocytes and GnRH neurons also use the RPTPβ/contactin/CASPR1 complex for mutual interactions.…”

“…In nonhuman primates, SynCAM1 expression increases in the hypothalamus at the time of female puberty [67], and the selective disruption of SynCAM1-dependent intracellular signaling in astrocytes delays puberty, disrupts estrous cyclicity and reduces fecundity in mice [68]. Importantly, the SynCAM1 and erbB4 signaling pathways are functionally coupled in hypothalamic astrocytes.…”

“…Importantly, the SynCAM1 and erbB4 signaling pathways are functionally coupled in hypothalamic astrocytes. The ligand-induced activation of erbB4 receptors promotes the physical interaction of erbB4 and SynCAM1 through their intracellular domains, activates SynCAM1 gene transcription and stimulates its adhesive behavior [66,68]. SynCAM1 is in turn necessary for neuregulin-dependent erbB4 activation to elicit PGE2 release from astrocytes and GnRH release from nerve terminals [68].…”

“…The ligand-induced activation of erbB4 receptors promotes the physical interaction of erbB4 and SynCAM1 through their intracellular domains, activates SynCAM1 gene transcription and stimulates its adhesive behavior [66,68]. SynCAM1 is in turn necessary for neuregulin-dependent erbB4 activation to elicit PGE2 release from astrocytes and GnRH release from nerve terminals [68]. It appears, therefore, that erbB4 and SynCAM1 form a signaling complex in hypothalamic astrocytes that is activated at puberty and promotes female reproductive capacity by jointly regulating adhesive and paracrine communication between astrocytes and GnRH neurons.…”

Neuroendocrine integration of nutritional signals on reproduction

“…Furthermore, Sandau and coworkers demonstrated that the synaptic cell adhesion molecule, SynCAM1, mediates astrocyte-to-GNRH neuron adhesiveness in the mouse hypothalamus (Sandau et al 2011b), and it was shown that astrocyte-to-GNRH neuron adhesiveness via SynCAM1 is important in the control of female sexual development. For example, female mice expressing a SynCAM1 dominant negative form specifically in astrocytes exhibited delayed onset of puberty, disrupted estrus cyclicity and reduced fecundity (Sandau et al 2011a). Astroglial cells, therefore, play a role in GNRH neuronal function and may facilitate the nutritional regulation of fertility.…”