Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes

Vincent Prevot, Carlos Rio, Gyeong J. Cho, Alejandro Lomniczi, Sabine Heger, Craig M. Neville, Nadia A. Rosenthal, Sergio Ojeda, Gabriel Corfas

    Research output: Contribution to journalArticle

    127 Citations (Scopus)

    Abstract

    The initiation of mammalian puberty requires the activation of hypothalamic neurons secreting the neuropeptide luteinizing hormone-releasing hormone (LHRH). It is thought that this activation is caused by changes in trans-synaptic input to LHRH neurons. More recently, it has been postulated that the pubertal increase in LHRH secretion in female animals also requires neuron-glia signaling mediated by growth factors of the epidermal growth factor (EGF) family and their astrocytic erbB receptors. Although it appears clear that functional astrocytic erbB1 receptors are necessary for the timely advent of puberty, the physiological contribution that erbB4 receptors may make to this process has not been established. To address this issue, we generated transgenic mice expressing a dominant-negative erbB4 receptor (DN-erbB4) under the control of the GFAP promoter, which targets transgene expression to astrocytes. DN-erbB4 expression is most abundant in hypothalamic astrocytes, where it blocks the ligand-dependent activation of glial erbB4 and erbB2 receptors, without affecting erbB1 (EGF) receptor signaling. Mice carrying the transgene exhibit delayed sexual maturation and a diminished reproductive capacity in early adulthood. These abnormalities are related to a deficiency in pituitary gonadotropin hormone secretion, caused by impaired release of LHRH, the hypothalamic neuropeptide that controls sexual development. In turn, the reduction in LHRH release is caused by the inability of hypothalamic astrocytes to respond to neuregulin (NRG) with production of prostaglandin E2, which in wild-type animals mediates the stimulatory effect of astroglial erbB receptor activation on neuronal LHRH release. Thus, neuron-astroglia communication via NRG-erbB4/2 receptor signaling appears to be essential for the timely unfolding of the developmental program by which the brain controls mammalian sexual maturation.

    Original languageEnglish (US)
    Pages (from-to)230-239
    Number of pages10
    JournalJournal of Neuroscience
    Volume23
    Issue number1
    StatePublished - Jan 1 2003

    Fingerprint

    Neuregulins
    Sexual Development
    Gonadotropin-Releasing Hormone
    Astrocytes
    Neurons
    Sexual Maturation
    Puberty
    Neuropeptides
    Transgenes
    Neuroglia
    Pituitary Gonadotropins
    Wild Animals
    Pituitary Hormones
    Epidermal Growth Factor Receptor
    Dinoprostone
    Epidermal Growth Factor
    Transgenic Mice
    ErbB Receptors
    Intercellular Signaling Peptides and Proteins
    Communication

    Keywords

    • Astrocytes
    • Hypothalamus
    • Mammalian puberty
    • Neuregulin
    • Neuroendocrine
    • Neuron-glia interactions

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Prevot, V., Rio, C., Cho, G. J., Lomniczi, A., Heger, S., Neville, C. M., ... Corfas, G. (2003). Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes. Journal of Neuroscience, 23(1), 230-239.

    Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes. / Prevot, Vincent; Rio, Carlos; Cho, Gyeong J.; Lomniczi, Alejandro; Heger, Sabine; Neville, Craig M.; Rosenthal, Nadia A.; Ojeda, Sergio; Corfas, Gabriel.

    In: Journal of Neuroscience, Vol. 23, No. 1, 01.01.2003, p. 230-239.

    Research output: Contribution to journalArticle

    Prevot, V, Rio, C, Cho, GJ, Lomniczi, A, Heger, S, Neville, CM, Rosenthal, NA, Ojeda, S & Corfas, G 2003, 'Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes', Journal of Neuroscience, vol. 23, no. 1, pp. 230-239.
    Prevot, Vincent ; Rio, Carlos ; Cho, Gyeong J. ; Lomniczi, Alejandro ; Heger, Sabine ; Neville, Craig M. ; Rosenthal, Nadia A. ; Ojeda, Sergio ; Corfas, Gabriel. / Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes. In: Journal of Neuroscience. 2003 ; Vol. 23, No. 1. pp. 230-239.
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    abstract = "The initiation of mammalian puberty requires the activation of hypothalamic neurons secreting the neuropeptide luteinizing hormone-releasing hormone (LHRH). It is thought that this activation is caused by changes in trans-synaptic input to LHRH neurons. More recently, it has been postulated that the pubertal increase in LHRH secretion in female animals also requires neuron-glia signaling mediated by growth factors of the epidermal growth factor (EGF) family and their astrocytic erbB receptors. Although it appears clear that functional astrocytic erbB1 receptors are necessary for the timely advent of puberty, the physiological contribution that erbB4 receptors may make to this process has not been established. To address this issue, we generated transgenic mice expressing a dominant-negative erbB4 receptor (DN-erbB4) under the control of the GFAP promoter, which targets transgene expression to astrocytes. DN-erbB4 expression is most abundant in hypothalamic astrocytes, where it blocks the ligand-dependent activation of glial erbB4 and erbB2 receptors, without affecting erbB1 (EGF) receptor signaling. Mice carrying the transgene exhibit delayed sexual maturation and a diminished reproductive capacity in early adulthood. These abnormalities are related to a deficiency in pituitary gonadotropin hormone secretion, caused by impaired release of LHRH, the hypothalamic neuropeptide that controls sexual development. In turn, the reduction in LHRH release is caused by the inability of hypothalamic astrocytes to respond to neuregulin (NRG) with production of prostaglandin E2, which in wild-type animals mediates the stimulatory effect of astroglial erbB receptor activation on neuronal LHRH release. Thus, neuron-astroglia communication via NRG-erbB4/2 receptor signaling appears to be essential for the timely unfolding of the developmental program by which the brain controls mammalian sexual maturation.",
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