Epidermal growth factor tyrosine kinase receptors and the neuroendocrine control of mammalian puberty

In recent years evidence has begun to accumulate indicating that the central control of mammalian puberty requires not only changes in transsynaptic communication, but also the participation of glial cells. Neurons and astrocytes control the pubertal process by regulating the secretory activity of those neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide that governs sexual development. LHRH, in turn, directs sexual development by stimulating the secretion of pituitary gonadotropins. Astrocytes affect LHRH neuronal function via cell–cell signaling mechanisms involving several growth factors acting via receptors endowed with tyrosine kinase activity. We have identified two members of the epidermal growth factor/transforming growth factor alpha (EGF/TGF) family and their respective receptors as key players in the glial–neuronal interactive process that regulates LHRH secretion. Our results indicate that TGF and its distant congener neuregulin (NRG) are produced in hypothalamic astrocytes and stimulate LHRH release indirectly via activation of their respective receptors, located—surprisingly—not on LHRH neurons, but on astrocytes. Activation of EGF receptors by TGF, and/or the erbB2/erbB4 receptor complex by NRG, leads to glial release of prostaglandin (PG) E₂, which then acts directly on LHRH neurons to stimulate LHRH release. That a central blockade of TGF or NRG action delays puberty, and focal overexpression of TGF advances it, leads to the conclusion that both TGF and NRG are physiological components of the central mechanism controlling the initiation of female puberty.