Neuregulins signaling via a glial erbB-2-erbB-4 receptor complex contribute to the neuroendocrine control of mammalian sexual development

Ying J. Ma, Diane F. Hill, Kimberly E. Creswick, Maria E. Costa, Anda Cornea, Mario N. Lioubin, Gregory D. Plowman, Sergio R. Ojeda

Research output: Contribution to journalArticlepeer-review

105 Scopus citations


Activation of erbB-1 receptors by glial TGFα has been shown to be a component of the developmental program by which the neuroendocrine brain controls mammalian sexual development. The participation of other members of the erbB family may be required, however, for full signaling capacity. Here, we show that activation of astrocytic erbB-2/erbB-4 receptors plays a significant role in the process by which the hypothalamus controls the advent of mammalian sexual maturation. Hypothalamic astrocytes express both the erbB-2 and erbB-4 genes, but no erbB-3, and respond to neuregulins (NRGs) by releasing prostaglandin E2 (PGE2), which acts on neurosecretory neurons to stimulate secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development. The actions of TGFα and NRGs in glia are synergistic and involve recruitment of erbB-2 as a coreceptor, via erbB-1 and erbB-4, respectively. Hypothalamic expression of both erbB-2 and erbB-4 increases first in a gonad-independent manner before the onset of puberty, and then, at the time of puberty, in a sex steroid-dependent manner. Disruption of erbB-2 synthesis in hypothalamic astrocytes by treatment with an antisense oligodeoxynucleotide inhibited the astrocytic response to NRGs and, to a lesser extent, that to TGFα and blocked the erbB-dependent, glia- mediated, stimulation of LHRH release. Intracerebral administration of the oligodeoxynucleotide to developing animals delayed the initiation of puberty. Thus, activation of the erbB-2-erbB-4 receptor complex appears to be a critical component of the signaling process by which astrocytes facilitate the acquisition of female reproductive capacity in mammals.

Original languageEnglish (US)
Pages (from-to)9913-9927
Number of pages15
JournalJournal of Neuroscience
Issue number22
StatePublished - Nov 15 1999
Externally publishedYes


  • Astroglial cells
  • Female sexual development
  • Glial growth factors
  • Hypothalamus
  • Puberty
  • Tyrosine kinase receptors

ASJC Scopus subject areas

  • Neuroscience(all)


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