Region-specific regulation of transforming growth factor alpha (TGF alpha) gene expression in astrocytes of the neuroendocrine brain

Abstract

Certain glial cells of the hypothalamus have been implicated in the neuroendocrine control of reproductive development. Hypothalamic astrocytes appear to exert this function via a cell-cell interactive mechanism that involves the production of transforming growth factor alpha (TGF alpha), a polypeptide able to affect both glial and neuronal functions in the CNS. In the hypothalamus, TGF alpha stimulates neuronal secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development, via activation of epidermal growth factor receptors (EGFR). Since astrocytes but not LHRH neurons express EGFR, it has been postulated that the stimulatory effect of TGF alpha on LHRH release is not exerted directly on LHRH neurons, but rather via glial intermediacy. The present experiments were undertaken to define whether TGF alpha is able to exert paracrine/autocrine effects on isolated hypothalamic astrocytes, and to determine if estradiol-previously shown to increase TGF alpha mRNA levels in the hypothalamus of immature animals--can act directly on hypothalamic astrocytes to upregulate TGF alpha gene expression. Treatment with either TGF alpha or its structural homolog, epidermal growth factor (EGF), increased TGF alpha mRNA levels within 8 hr of exposure; the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was similarly effective. Blockade of EGFR with either tyrphostin RG-50864, an inhibitor of tyrosine kinase activity, or a monoclonal antibody that prevents ligand binding abolished the upregulatory effect of TGF alpha on TGF alpha mRNA levels. In contrast to hypothalamic astrocytes, cerebellar astrocytes did not respond to either TGF alpha or EGF with changes in TGF alpha mRNA abundance.(ABSTRACT TRUNCATED AT 250 WORDS)

The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty

“…8 ably due to retraction of the glial cells. 14 16 As glial-neuronal synaptoid specializations are commonly seen in the median emilogical blockade of EGFR tyrosine kinase activity 36 targeted to the median eminence delays the onset of nence, 12 this region appears to be a primary site where glial cells influence LHRH neuronal function. In this puberty, 23 suggesting that activation of EGFR in this region of the hypothalamus is a physiological compoarticle, we will discuss some of the recent results obtained by our laboratory concerning the potentially nent of the central mechanism underlying the acquisition of reproductive competence.…”

“…In one of them, fibroblasts were stably transfected with a retroviral construct in which role in the process by which astrocytes affect LHRH secretory activity. 16,[20][21][22][23][24] More recently, we obtained expression of the human TGF␣ gene was directed by the phosphoglycerate kinase promoter, which is constievidence for the involvement of other members of the EGF/TGF␣ family in this process. Neuregulins, also tutively active in most mammalian cells.…”

“…That TGF␣ may be involved in the control of LHRH neuronal activity are not exerted directly, as LHRH neurons do not contain EGFR. 22 Instead, TGF␣ acts on hypothalactivity was demonstrated by the finding that TGF␣ is able to stimulate the release of LHRH from median emiamic astrocytes, which are endowed with EGFR, 16,38 and respond to the peptide with an increase in TGF␣ nence fragments in a dose-related manner. 35 Several observations suggest that TGF␣-induced activation of gene expression 16 and PGE 2 release.…”

“…22 Instead, TGF␣ acts on hypothalactivity was demonstrated by the finding that TGF␣ is able to stimulate the release of LHRH from median emiamic astrocytes, which are endowed with EGFR, 16,38 and respond to the peptide with an increase in TGF␣ nence fragments in a dose-related manner. 35 Several observations suggest that TGF␣-induced activation of gene expression 16 and PGE 2 release. 39 The conditioned medium from hypothalamic astrocytes treated with EGFR contributes to the normal initiation of mammalian female puberty.…”

“…39 Population Center Grant HD18185, and RR00163 for In addition to TGF␣ itself, glial expression of the the operation of the ORPRC. TGF␣ gene appears to be upregulated by gonadal steroids (estrogen) and neuronal inputs (excitatory amino acids), 16,40 suggesting that in addition to the above outReferences lined glial-neuronal signaling pathway mediated by…”