Normal Female Sexual Development Requires Neuregulin–erbB Receptor Signaling in Hypothalamic Astrocytes

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 E(2), 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.

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

“…ErbB4 receptors have either not been detected (Prevot et al, 2003) or TGFa is a gliatrophin for astrocytes A Sharif et al were observed at low levels (Elenius et al, 1997;Francis et al, 1999) in astrocytes cultures derived from newborn rat cortices. ErbB3 expression has been found in one study (Francis et al, 1999) and not in another (Pinkas-Kramarski et al, 1997).…”

Prostaglandin E 2 release from astrocytes triggers gonadotropin-releasing hormone (GnRH) neuron firing via EP2 receptor activation

“…It is now clear that the secretory activity of GnRH neurons is controlled by both neuronal and glial input (12,13,15,16). Whereas glutamate is a key neurotransmitter involved in the transsynaptic activation of GnRH neurons (17, 18), prostaglandin E 2 (PGE 2 ) mediates cell-cell communication between astrocytes and GnRH neurons (6,19,20). A functional connection between the two systems is demonstrated by the ability of glutamate to elicit PGE 2 release from astrocytes (21-23).…”

“…I t is increasingly clear that astrocytes play an important role in maintaining central nervous system function (1-3) and controlling key bodily processes, such as breathing (4), sleep (5), and reproduction (6). Because of their perivascular and interneuronal localization, astrocytes are well positioned to sense afferent neuronal and blood-borne signals and ideally suited for the temporal and spatial propagation of these signals (7)(8)(9).…”

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

“…DNerbB4 is a truncated receptor lacking the tyrosine kinase domain and phosphorylation sites (20). DN-erbB4 expression completely blocks erbB2, erbB3, and erbB4 receptor signaling (18,20,21) without affecting signaling by other receptors, e.g., the EGF receptor, an erbB family member (21). Two Tg lines that express high levels of DN-erbB4, CNP3 and CNP48, were characterized and exhibited similar phenotypes.…”