Activation of erbB-1 Signaling in Tanycytes of the Median Eminence Stimulates Transforming Growth Factor β1 Release via Prostaglandin E2 Production and Induces Cell Plasticity

Abstract

The activation of transforming growth factor α (TGFα)-erbB-1 and neuregulin-erbB-4 signaling pathways in hypothalamic astrocytes has been shown to play a key role in the process by which the neuroendocrine brain controls luteinizing hormone-releasing hormone (LHRH) secretion. Earlier studies suggested that tanycytes, an ependymoglial cell type of the median eminence, regulate LHRH release during the estrous cycle by undergoing plastic changes that alternatively allow or prevent direct access of the LHRH nerve terminals to the portal vasculature. Neither the molecules responsible for these plastic changes nor the underlying controlling mechanisms have been identified. Here we show that cultured tanycytes express erbB-1 and erbB-2, two of the four members of the erbB receptor family, and respond to TGFα with receptor phosphorylation, release of prostaglandin E2 (PGE 2), and a PGE2-dependent increase in the release of TGFβ1, a growth factor previously implicated in the glial control of LHRH secretion. Blockade of either erbB-1 receptor signal transduction or prostaglandin synthesis prevented the stimulatory effect of TGFα on both PGE2 and TGFβ1 release. Time-lapse studies revealed that TGFα and TGFβ1 have dramatically opposite effects on tanycyte plasticity. Whereas TGFα promotes tanycytic outgrowth, TGFβ1 elicits retraction of tanycytic processes. Blockade of metalloproteinase activity abolished the effect of TGFβ1, suggesting that TGFβ1 induces tanycytic retraction by facilitating dissolution of the extracellular matrix. Prolonged (> 12 hr) exposure of tanycytes to TGFα resulted in focal tanycytic retraction, an effect that was abolished by immunoneutralization of TGFβ1, action, indicating that the retraction was attributable to TGFα-induced TGFβ1 formation. These in vitro results identify tanycytes as targets of TGFα action and demonstrate that activation of erbB-1-mediated signaling in these cells results in plastic changes that, involving PGE2 and TGFβ1, as downstream effectors, mimic the morphological plasticity displayed by tanycytes during the hours encompassing the preovulatory surge of LHRH.