Targeting transforming growth factor α expression to discrete loci of the neuroendocrine brain induces female sexual precocity

F. Rage, D. F. Hill, M. Sena-Esteves, X. O. Breakefield, R. J. Coffey, M. E. Costa, S. M. McCann, Sergio Ojeda

    Research output: Contribution to journalArticle

    61 Citations (Scopus)

    Abstract

    Precocious puberty of cerebral origin is a poorly understood disorder of human sexual development, brought about by the premature activation of those neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual maturation. An increased production of transforming growth factor α (TGFα) in the hypothalamus has been implicated in the mechanism underlying both normal and precocious puberty. We have now used two gene delivery systems to target TGFα overexpression near LHRH neurons in immature female rats. Fibroblasts infected with a retroviral construct in which expression of the human TGFα gene is constitutively driven by the phosphoglycerate kinase promoter, or transfected with a plasmid in which TGFα expression is controlled by an inducible metallothionein promoter, were transplanted into several regions of the hypothalamus. When the cells were in contact with LHRH nerve terminals or in the vicinity of LHRH perikarya, sexual maturation was accelerated. These results suggest that precocious puberty of cerebral origin may result from a focal disorder of TGFα production within the confines of the LHRH neuron microenvironment.

    Original languageEnglish (US)
    Pages (from-to)2735-2740
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume94
    Issue number6
    DOIs
    StatePublished - 1997

    Fingerprint

    Transforming Growth Factors
    Gonadotropin-Releasing Hormone
    Precocious Puberty
    Brain
    Sexual Maturation
    Neurons
    Hypothalamus
    Phosphoglycerate Kinase
    Disorders of Sex Development
    Gene Transfer Techniques
    Metallothionein
    Human Development
    Neuropeptides
    Plasmids
    Fibroblasts
    Sexual precocity
    Genes

    ASJC Scopus subject areas

    • Genetics
    • General

    Cite this

    Targeting transforming growth factor α expression to discrete loci of the neuroendocrine brain induces female sexual precocity. / Rage, F.; Hill, D. F.; Sena-Esteves, M.; Breakefield, X. O.; Coffey, R. J.; Costa, M. E.; McCann, S. M.; Ojeda, Sergio.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 6, 1997, p. 2735-2740.

    Research output: Contribution to journalArticle

    Rage, F. ; Hill, D. F. ; Sena-Esteves, M. ; Breakefield, X. O. ; Coffey, R. J. ; Costa, M. E. ; McCann, S. M. ; Ojeda, Sergio. / Targeting transforming growth factor α expression to discrete loci of the neuroendocrine brain induces female sexual precocity. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 6. pp. 2735-2740.
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    abstract = "Precocious puberty of cerebral origin is a poorly understood disorder of human sexual development, brought about by the premature activation of those neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual maturation. An increased production of transforming growth factor α (TGFα) in the hypothalamus has been implicated in the mechanism underlying both normal and precocious puberty. We have now used two gene delivery systems to target TGFα overexpression near LHRH neurons in immature female rats. Fibroblasts infected with a retroviral construct in which expression of the human TGFα gene is constitutively driven by the phosphoglycerate kinase promoter, or transfected with a plasmid in which TGFα expression is controlled by an inducible metallothionein promoter, were transplanted into several regions of the hypothalamus. When the cells were in contact with LHRH nerve terminals or in the vicinity of LHRH perikarya, sexual maturation was accelerated. These results suggest that precocious puberty of cerebral origin may result from a focal disorder of TGFα production within the confines of the LHRH neuron microenvironment.",
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    AU - Sena-Esteves, M.

    AU - Breakefield, X. O.

    AU - Coffey, R. J.

    AU - Costa, M. E.

    AU - McCann, S. M.

    AU - Ojeda, Sergio

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