Involvement of transforming growth factor α in the release of luteinizing hormone-releasing hormone from the developing female hypothalamus

Sergio Ojeda, Henryk Urbanski, M. E. Costa, D. F. Hill, M. Moholt-Siebert

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    150 Citations (Scopus)

    Abstract

    Little is known about the presence of trophic factors in the hypothalamus and the role they may play in regulating the functional development of hypothalamic neurons. We have investigated the ability of epidermal growth factor (EGF) and transforming growth factor a (TGF-α) to affect the release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls reproductive development. We have also determined whether the genes encoding EGF and TGF-α are expressed in the prepubertal female hypothalamus. Northern blot analysis of poly(A)+ RNA utilizing a single-stranded EGF cDNA probe failed to reveal the presence of EGF mRNA in either the hypothalamus or the cerebral cortex at any age studied (fetal day 18 to postnatal day 36). In contrast, both a complementary RNA probe and a double-stranded TGF-α cDNA recognized in these regions a 4.5-kilobase (kb) mRNA species identical to TGF-α mRNA. The abundance of TGF-α mRNA was 3-4 times greater in the hypothalamus than in the cerebral cortex. Both EGF and TGF-α (2-100 ng/ml) elicited a dose-related increase in LHRH release from the median eminence of juvenile rats in vitro. They also enhanced prostaglandin E2 (PGE2) release. The transforming growth factors TGF-β1 and -β2 were ineffective. Only a high dose of basic fibroblast growth factor was able to increase LHRH and PGE2 release. Blockade of the EGF receptor transduction mechanism with RG 50864, a selective inhibitor of EGF receptor tyrosine kinase activity, prevented the effect of both EGF and TGF-α on LHRH and PGE2 release but failed to inhibit the stimulatory effect of PGE2 on LHRH release. Inhibition of prostaglandin synthesis abolished the effect of TGF-α on LHRH, indicating that PGE2 mediates TGF-α-induced LHRH release. The results indicate that the effect of EGF and TGF-α on LHRH release is mediated by the EGF/TGF-α receptor and suggest that TGF-α rather than EGF may be the physiological ligand for this interaction. Since in the central nervous system most EGF/TGF-α receptors are located on glial cells, the results also raise the possibility that - at the median eminence - TGF-α action may involve a glial-neuronal interaction, a mechanism by which the trophic factor first stimulates PGE2 release from glial cells, and then PGE2 elicits LHRH from the neuronal terminals.

    Original languageEnglish (US)
    Pages (from-to)9698-9702
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume87
    Issue number24
    StatePublished - 1990

    Fingerprint

    Transforming Growth Factors
    Gonadotropin-Releasing Hormone
    Hypothalamus
    Epidermal Growth Factor
    Dinoprostone
    Messenger RNA
    Neuroglia
    Median Eminence
    Growth Factor Receptors
    Epidermal Growth Factor Receptor
    Cerebral Cortex
    Complementary DNA
    RNA Probes
    Complementary RNA
    Fibroblast Growth Factor 2
    Neuropeptides
    Northern Blotting
    Protein-Tyrosine Kinases
    Gestational Age
    Prostaglandins

    Keywords

    • Median eminence
    • Neuropeptide release
    • Prostaglandin e
    • Trophic interactions

    ASJC Scopus subject areas

    • Genetics
    • General

    Cite this

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    abstract = "Little is known about the presence of trophic factors in the hypothalamus and the role they may play in regulating the functional development of hypothalamic neurons. We have investigated the ability of epidermal growth factor (EGF) and transforming growth factor a (TGF-α) to affect the release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls reproductive development. We have also determined whether the genes encoding EGF and TGF-α are expressed in the prepubertal female hypothalamus. Northern blot analysis of poly(A)+ RNA utilizing a single-stranded EGF cDNA probe failed to reveal the presence of EGF mRNA in either the hypothalamus or the cerebral cortex at any age studied (fetal day 18 to postnatal day 36). In contrast, both a complementary RNA probe and a double-stranded TGF-α cDNA recognized in these regions a 4.5-kilobase (kb) mRNA species identical to TGF-α mRNA. The abundance of TGF-α mRNA was 3-4 times greater in the hypothalamus than in the cerebral cortex. Both EGF and TGF-α (2-100 ng/ml) elicited a dose-related increase in LHRH release from the median eminence of juvenile rats in vitro. They also enhanced prostaglandin E2 (PGE2) release. The transforming growth factors TGF-β1 and -β2 were ineffective. Only a high dose of basic fibroblast growth factor was able to increase LHRH and PGE2 release. Blockade of the EGF receptor transduction mechanism with RG 50864, a selective inhibitor of EGF receptor tyrosine kinase activity, prevented the effect of both EGF and TGF-α on LHRH and PGE2 release but failed to inhibit the stimulatory effect of PGE2 on LHRH release. Inhibition of prostaglandin synthesis abolished the effect of TGF-α on LHRH, indicating that PGE2 mediates TGF-α-induced LHRH release. The results indicate that the effect of EGF and TGF-α on LHRH release is mediated by the EGF/TGF-α receptor and suggest that TGF-α rather than EGF may be the physiological ligand for this interaction. Since in the central nervous system most EGF/TGF-α receptors are located on glial cells, the results also raise the possibility that - at the median eminence - TGF-α action may involve a glial-neuronal interaction, a mechanism by which the trophic factor first stimulates PGE2 release from glial cells, and then PGE2 elicits LHRH from the neuronal terminals.",
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    T1 - Involvement of transforming growth factor α in the release of luteinizing hormone-releasing hormone from the developing female hypothalamus

    AU - Ojeda, Sergio

    AU - Urbanski, Henryk

    AU - Costa, M. E.

    AU - Hill, D. F.

    AU - Moholt-Siebert, M.

    PY - 1990

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    N2 - Little is known about the presence of trophic factors in the hypothalamus and the role they may play in regulating the functional development of hypothalamic neurons. We have investigated the ability of epidermal growth factor (EGF) and transforming growth factor a (TGF-α) to affect the release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls reproductive development. We have also determined whether the genes encoding EGF and TGF-α are expressed in the prepubertal female hypothalamus. Northern blot analysis of poly(A)+ RNA utilizing a single-stranded EGF cDNA probe failed to reveal the presence of EGF mRNA in either the hypothalamus or the cerebral cortex at any age studied (fetal day 18 to postnatal day 36). In contrast, both a complementary RNA probe and a double-stranded TGF-α cDNA recognized in these regions a 4.5-kilobase (kb) mRNA species identical to TGF-α mRNA. The abundance of TGF-α mRNA was 3-4 times greater in the hypothalamus than in the cerebral cortex. Both EGF and TGF-α (2-100 ng/ml) elicited a dose-related increase in LHRH release from the median eminence of juvenile rats in vitro. They also enhanced prostaglandin E2 (PGE2) release. The transforming growth factors TGF-β1 and -β2 were ineffective. Only a high dose of basic fibroblast growth factor was able to increase LHRH and PGE2 release. Blockade of the EGF receptor transduction mechanism with RG 50864, a selective inhibitor of EGF receptor tyrosine kinase activity, prevented the effect of both EGF and TGF-α on LHRH and PGE2 release but failed to inhibit the stimulatory effect of PGE2 on LHRH release. Inhibition of prostaglandin synthesis abolished the effect of TGF-α on LHRH, indicating that PGE2 mediates TGF-α-induced LHRH release. The results indicate that the effect of EGF and TGF-α on LHRH release is mediated by the EGF/TGF-α receptor and suggest that TGF-α rather than EGF may be the physiological ligand for this interaction. Since in the central nervous system most EGF/TGF-α receptors are located on glial cells, the results also raise the possibility that - at the median eminence - TGF-α action may involve a glial-neuronal interaction, a mechanism by which the trophic factor first stimulates PGE2 release from glial cells, and then PGE2 elicits LHRH from the neuronal terminals.

    AB - Little is known about the presence of trophic factors in the hypothalamus and the role they may play in regulating the functional development of hypothalamic neurons. We have investigated the ability of epidermal growth factor (EGF) and transforming growth factor a (TGF-α) to affect the release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls reproductive development. We have also determined whether the genes encoding EGF and TGF-α are expressed in the prepubertal female hypothalamus. Northern blot analysis of poly(A)+ RNA utilizing a single-stranded EGF cDNA probe failed to reveal the presence of EGF mRNA in either the hypothalamus or the cerebral cortex at any age studied (fetal day 18 to postnatal day 36). In contrast, both a complementary RNA probe and a double-stranded TGF-α cDNA recognized in these regions a 4.5-kilobase (kb) mRNA species identical to TGF-α mRNA. The abundance of TGF-α mRNA was 3-4 times greater in the hypothalamus than in the cerebral cortex. Both EGF and TGF-α (2-100 ng/ml) elicited a dose-related increase in LHRH release from the median eminence of juvenile rats in vitro. They also enhanced prostaglandin E2 (PGE2) release. The transforming growth factors TGF-β1 and -β2 were ineffective. Only a high dose of basic fibroblast growth factor was able to increase LHRH and PGE2 release. Blockade of the EGF receptor transduction mechanism with RG 50864, a selective inhibitor of EGF receptor tyrosine kinase activity, prevented the effect of both EGF and TGF-α on LHRH and PGE2 release but failed to inhibit the stimulatory effect of PGE2 on LHRH release. Inhibition of prostaglandin synthesis abolished the effect of TGF-α on LHRH, indicating that PGE2 mediates TGF-α-induced LHRH release. The results indicate that the effect of EGF and TGF-α on LHRH release is mediated by the EGF/TGF-α receptor and suggest that TGF-α rather than EGF may be the physiological ligand for this interaction. Since in the central nervous system most EGF/TGF-α receptors are located on glial cells, the results also raise the possibility that - at the median eminence - TGF-α action may involve a glial-neuronal interaction, a mechanism by which the trophic factor first stimulates PGE2 release from glial cells, and then PGE2 elicits LHRH from the neuronal terminals.

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