This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Prevot, V. Articles by Ojeda, S. R. Search for Related Content PubMed PubMed Citation Articles by Prevot, V. Articles by Ojeda, S. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

erbB-1 and erbB-4 Receptors Act in Concert to Facilitate Female Sexual Development and Mature Reproductive Function

Division of Neuroscience (V.P., A.L., S.R.O.), Oregon National Primate Research Center/Oregon Health & Sciences University, Beaverton, Oregon 97006; and Division of Neuroscience (G.C.), Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Sergio R. Ojeda, Division of Neuroscience, Oregon National Primate Research Center, 505 Northwest 185th Avenue, Beaverton, Oregon 97006. E-mail: ojedas{at}ohsu.edu.

Glial erbB-1 and erbB-4 receptors are key components of the process by which neuroendocrine glial cells control LHRH secretion and the onset of female puberty. We now provide evidence that these two signaling systems work in a coordinated fashion to control reproductive function. To generate animals carrying functionally impaired erbB-1 and erbB-4 receptors, we crossed Waved 2 (Wa-2^+/+) mice harboring a point mutation of the erbB-1 receptor with mice expressing a dominant-negative erbB-4 receptor in astrocytes. In comparison to single-deficient mice, double-mutant animals exhibited a further delay in the onset of puberty and a strikingly diminished adult reproductive capacity. Ligand-dependent erbB receptor phosphorylation and erbB-mediated MAPK (ERK 1/2) phosphorylation were impaired in mutant astrocytes. Wa-2^+/+ or double-mutant astrocytes failed to respond to TGF with production of prostaglandin E₂, one of the factors mediating the stimulatory effect of astroglial erbB receptor activation on LHRH release. Medium conditioned by Wa-2^+/+ or double-mutant astrocytes treated with TGF failed to stimulate LHRH release from GT1–7 cells. The LH response to ovariectomy was significantly attenuated in mutant mice in comparison with wild-type controls. Although the Wa-2 mutation affects all cells bearing erbB-1 receptors, these results suggest that a major defect underlying the reproductive defects of animals with impaired erbB signaling is a decreased ability of glial cells to stimulate LHRH release. Thus, a coordinated involvement of erbB-1 and erbB-4 signaling systems is required for the normalcy of sexual development and the maintenance of mature female reproductive function.

This article has been cited by other articles:

				J. Dackor, K. M. Caron, and D. W. Threadgill Placental and Embryonic Growth Restriction in Mice With Reduced Function Epidermal Growth Factor Receptor Alleles Genetics, September 1, 2009; 183(1): 207 - 218. [Abstract] [Full Text] [PDF]

				A. A Gratao, M. Dahlhoff, F. Sinowatz, E. Wolf, and M. R Schneider Betacellulin Overexpression in the Mouse Ovary Leads to MAPK3/MAPK1 Hyperactivation and Reduces Litter Size by Impairing Fertilization Biol Reprod, January 1, 2008; 78(1): 43 - 52. [Abstract] [Full Text] [PDF]

				T. Takagi, T. Yamamura, T. Anraku, S. Yasuo, N. Nakao, M. Watanabe, M. Iigo, S. Ebihara, and T. Yoshimura Involvement of Transforming Growth Factor {alpha} in the Photoperiodic Regulation of Reproduction in Birds Endocrinology, June 1, 2007; 148(6): 2788 - 2792. [Abstract] [Full Text] [PDF]

				M. Hsieh, D. Lee, S. Panigone, K. Horner, R. Chen, A. Theologis, D. C. Lee, D. W. Threadgill, and M. Conti Luteinizing Hormone-Dependent Activation of the Epidermal Growth Factor Network Is Essential for Ovulation Mol. Cell. Biol., March 1, 2007; 27(5): 1914 - 1924. [Abstract] [Full Text] [PDF]

				M. Conti, M. Hsieh, J.-Y. Park, and Y.-Q. Su Role of the Epidermal Growth Factor Network in Ovarian Follicles Mol. Endocrinol., April 1, 2006; 20(4): 715 - 723. [Abstract] [Full Text] [PDF]

				S. R. Ojeda, A. Lomniczi, C. Mastronardi, S. Heger, C. Roth, A.-S. Parent, V. Matagne, and A. E. Mungenast Minireview: The Neuroendocrine Regulation of Puberty: Is the Time Ripe for a Systems Biology Approach? Endocrinology, March 1, 2006; 147(3): 1166 - 1174. [Abstract] [Full Text] [PDF]

				A. Lomniczi, A. Cornea, M. E. Costa, and S. R. Ojeda Hypothalamic Tumor Necrosis Factor-{alpha} Converting Enzyme Mediates Excitatory Amino Acid-Dependent Neuron-to-Glia Signaling in the Neuroendocrine Brain J. Neurosci., January 4, 2006; 26(1): 51 - 62. [Abstract] [Full Text] [PDF]

				S.-K. Han, M. L. Gottsch, K. J. Lee, S. M. Popa, J. T. Smith, S. K. Jakawich, D. K. Clifton, R. A. Steiner, and A. E. Herbison Activation of Gonadotropin-Releasing Hormone Neurons by Kisspeptin as a Neuroendocrine Switch for the Onset of Puberty J. Neurosci., December 7, 2005; 25(49): 11349 - 11356. [Abstract] [Full Text] [PDF]