Hypothalamic Tumor Necrosis Factor-α Converting Enzyme Mediates Excitatory Amino Acid-Dependent Neuron-to-Glia Signaling in the Neuroendocrine Brain

Abstract

Glial erbB1 receptors play a significant role in the hypothalamic control of female puberty. Activation of these receptors by transforming growth factor ␣ (TGF␣) results in production of prostaglandin E 2 , which then stimulates luteinizing hormone releasing hormone (LHRH) neurons to secrete LHRH, the neuropeptide controlling sexual development. Glutamatergic neurons set in motion this glia-toneuron signaling pathway by transactivating erbB1 receptors via coactivation of AMPA receptors (AMPARs) and metabotropic glutamate receptors (mGluRs). Because the metalloproteinase tumor necrosis factor ␣ converting enzyme (TACE) releases TGF␣ from its transmembrane precursor before TGF␣ can bind to erbB1 receptors, we sought to determine whether TACE is required for excitatory amino acids to activate the TGF␣-erbB1 signaling module in hypothalamic astrocytes, and thus facilitate the advent of puberty. Coactivation of astrocytic AMPARs and mGluRs caused extracellular Ca 2ϩ influx, a Ca 2ϩ /protein kinase C-dependent increase in TACE-like activity, and enhanced release of TGF␣. Within the hypothalamus, TACE is most abundantly expressed in astrocytes of the median eminence (ME), and its enzymatic activity increases selectively in this region at the time of the first preovulatory surge of gonadotropins. ME explants respond to stimulation of AMPARs and mGluRs with LHRH release, and this response is prevented by blocking TACE activity. In vivo inhibition of TACE activity targeted to the ME delayed the age at first ovulation, indicating that ME-specific changes in TACE activity are required for the normal timing of puberty. These results suggest that TACE is a component of the neuron-to-glia signaling process used by glutamatergic neurons to control female sexual development.

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

“…In particular, the metalloproteinase ADAM17, also known as TACE is involved in the processing of pro-TGFα. TGFα and NRG then activate erbB1/erbB2 and erbB4/erbB2 heterodimers, respectively, leading to the production of PGE2 by COX and its subsequent release from astrocytes [19,20,22,26]. PGE2 is also released upon the activation of the G protein-coupled oxytocin receptors (OT-R), which are located on hypothalamic astrocytes.…”

“…Moreover, this astrocyte-to-neuron signaling pathway has been shown to be set in motion by glutamate. The concomitant activation of ionotropic and metabotropic glutamate receptors located on astroglial cells stimulates erbB signaling by favoring the redistribution of TGFα-erbB1 and NRG-erbB4 complexes to the cell membrane and the subsequent metalloproteinase (MMP)-dependent transactivation of receptors [19,26]. This link between glutamate receptors and erbB signaling in astrocytes could represent a mechanism used by the neuroendocrine brain to coordinate the enhanced glutamatergic neurotransmission and glial back-signaling to GnRH neurons required for the timely onset of mammalian puberty [2].…”

“…This link between glutamate receptors and erbB signaling in astrocytes could represent a mechanism used by the neuroendocrine brain to coordinate the enhanced glutamatergic neurotransmission and glial back-signaling to GnRH neurons required for the timely onset of mammalian puberty [2]. The in vivo significance of the EGF signaling pathway in controlling GnRH function is suggested by experiments showing that the expression of TGFα, erbB1, erbB2, erbB4 and the enzymatic activity of tumor necrosis factor-α-converting enzyme (TACE), a metalloproteinase involved in the ectodomain shedding of TGFα and the subsequent activation of erbB1 in response to glutamatergic inputs [26], increase in the hypothalamus at the time of puberty [20,24,26,27,28]. Moreover, the in vivo deregulation of TGFα/erbB1 [23,27,29,30,31,32] or erbB2 signaling [20], or the inhibition of TACE activity [26], perturbs the onset of female puberty.…”

“…The in vivo significance of the EGF signaling pathway in controlling GnRH function is suggested by experiments showing that the expression of TGFα, erbB1, erbB2, erbB4 and the enzymatic activity of tumor necrosis factor-α-converting enzyme (TACE), a metalloproteinase involved in the ectodomain shedding of TGFα and the subsequent activation of erbB1 in response to glutamatergic inputs [26], increase in the hypothalamus at the time of puberty [20,24,26,27,28]. Moreover, the in vivo deregulation of TGFα/erbB1 [23,27,29,30,31,32] or erbB2 signaling [20], or the inhibition of TACE activity [26], perturbs the onset of female puberty. The crucial role of astrocytic erbB signaling in the control of reproductive function has been demonstrated in transgenic mice expressing a dominant-negative erbB4 receptor in astrocytes, which selectively blocks the ligand-dependent activation of erbB4 and erbB2 receptors in these cells [21].…”

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

“…One mechanism by which SynCAM1 regulates excitatory neurotransmission is through the recruitment of N-methyl-D-aspartate or 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid receptors via the intracellular FERM binding domain of SynCAM1 (44). Hypothalamic astrocytes express both metabotropic glutamate and 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid receptors, which upon activation initiate a signaling cascade that leads to erbB receptor activation and glia-to-neuron signaling events required for normal reproductive development (45,46). Therefore, it is tempting to speculate that astroglial SynCAM1 may act as an adhesion/signaling molecule able to organize excitatory neuronto-glia signaling domains in hypothalamic astrocytes.…”