Hypothalamic lesions that induce female precocious puberty activate glial expression of the epidermal growth factor receptor gene: Differential regulation of alternatively spliced transcripts

Marie Pierre Junier, Diane F. Hill, Maria E. Costa, Stephen Felder, Sergio Ojeda

    Research output: Contribution to journalArticle

    63 Citations (Scopus)

    Abstract

    Injury of the nervous system triggers a complex series of mechanisms that include production of neurotrophic and mitogenic factors by cells neighboring the injured area. While trauma of most parts of the brain results in loss of function, lesions of certain regions of the female hypothal-amus enhance the secretory activity of a group of special-and neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls sexual development. The increased output of LHRH causes sexual preococity by prematurely activating the neuroendocrine reproductive axis. Recent studies have implicated transforming growth factor α (TGFα) produced by reactive astrocytes in the process by which lesions hasten sexual maturation, and have suggested that the stimulatory actions of TGFα on LHRH neurons require the intermediacy of epidermal growth factor receptors (EGFRs). In the present study, we examined the changes in EGFR gene expression following lesions of the preoptic-anterior hypothalamic area (POA-AHA) of immature female rats, identified the cell types where EGFR synthesis increases, and assessed the biochemical activity of the newly formed EGFR protein. RNase protection assays demonstrated that the lesion significantly increased the levels of a predominant mRNA transcript encoding the full-length, membrane-spanning EGFR, but did not affect those of a much less abundant, alternatively spliced mRNA that encodes a truncated, presumably secreted form of EGFR. Following lesions, antibody-induced EGFR kinase activity increased twofold. Antibodies directed against a peptide sequence contained within the carboxy terminus of EGFR showed intense EGFR immunoreactivity in cells surrounding the lesion site; double immunohistochemistry identified these cells as astrocytes since EGFR immunoreactivity was colocalized with that of glial fibrillary acidic protein, an astrocytic marker. That these changes result from an increase in EGFR gene expression was indicated by the elevated levels of EGFR mRNA detected by in situ hybridization in cells of the same area. Although POA-AHA lesions did not result in appearance of EGFR in LHRH neurons themselves, EGFR-positive cells and processes were seen in close proximity to LHRH neurons and their nerve terminals, particularly in the area surrounding the lesion. Since TGFα gene expression is also increased in reactive astrocytes of POA-AHA lesions and blockade of EGFR prevented the advancing effect of the lesion on puberty (Junier et al., 1991b), the present results support the concept that, in lesioned animals, TGFα stimulates LHRH secretion indirectly via a paracrine mechanism that involves its interaction with EGFRs located on astroglial cells.

    Original languageEnglish (US)
    Pages (from-to)703-713
    Number of pages11
    JournalJournal of Neuroscience
    Volume13
    Issue number2
    StatePublished - 1993

    Fingerprint

    erbB-1 Genes
    Precocious Puberty
    Neuroglia
    Gonadotropin-Releasing Hormone
    Transforming Growth Factors
    Astrocytes
    Neurons
    Gene Expression
    ErbB Receptors
    Messenger RNA
    Anterior Hypothalamic Nucleus
    Nervous System Trauma
    Sexual Maturation
    Sexual Development
    Antibodies
    Glial Fibrillary Acidic Protein
    Nerve Growth Factors
    Puberty
    Ribonucleases
    Neuropeptides

    Keywords

    • Astrocytes
    • Epidermal growth factor receptor mRNA transcripts
    • Glial-neuronal interaction
    • Hypothalamic injury
    • Peptidergic neurons
    • Sexual precocity

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Hypothalamic lesions that induce female precocious puberty activate glial expression of the epidermal growth factor receptor gene : Differential regulation of alternatively spliced transcripts. / Junier, Marie Pierre; Hill, Diane F.; Costa, Maria E.; Felder, Stephen; Ojeda, Sergio.

    In: Journal of Neuroscience, Vol. 13, No. 2, 1993, p. 703-713.

    Research output: Contribution to journalArticle

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