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Journal of Neuroscience, Vol 13, 703-713, Copyright © 1993 by Society for Neuroscience

ARTICLE

Hypothalamic lesions that induce female precocious puberty activate glial expression of the epidermal growth factor receptor gene: differential regulation of alternatively spliced transcripts

MP Junier, DF Hill, ME Costa, S Felder and SR Ojeda
Division of Neuroscience, Oregon Regional Primate Research Center, Beaverton 97006.

Injury of the nervous system triggers a complex series of repair mechanisms that include production of neurotrophic and mitogenic factors by cells neighboring the injured area. While trauma of most parts of the brain results in loss of function, lesions of certain regions of the female hypothalamus enhance the secretory activity of a group of specialized neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls sexual development. The increased output of LHRH causes sexual precocity by prematurely activating the neuroendocrine reproductive axis. Recent studies have implicated transforming growth factor alpha (TGF alpha) produced by reactive astrocytes in the process by which lesions hasten sexual maturation, and have suggested that the stimulatory actions of TGF alpha on LHRH neurons require the intermediacy of epidermal growth factor receptors (EGFRs). In the present study, we examined the changes in EGFR gene expression following lesions of the preoptic-anterior hypothalamic area (POA-AHA) of immature female rats, identified the cell types where EGFR synthesis increases, and assessed the biochemical activity of the newly formed EGFR protein. RNase protection assays demonstrated that the lesion significantly increased the levels of a predominant mRNA transcript encoding the full-length, membrane-spanning EGFR, but did not affect those of a much less abundant, alternatively spliced mRNA that encodes a truncated, presumably secreted form of EGFR. Following lesions, antibody-induced EGFR kinase activity increased twofold. Antibodies directed against a peptide sequence contained within the carboxy terminus of EGFR showed intense EGFR immunoreactivity in cells surrounding the lesion site; double immunohistochemistry identified these cells as astrocytes since EGFR immunoreactivity was colocalized with that of glial fibrillary acidic protein, an astrocytic marker. That these changes result from an increase in EGFR gene expression was indicated by the elevated levels of EGFR mRNA detected by in situ hybridization in cells of the same area. Although POA-AHA lesions did not result in appearance of EGFR in LHRH neurons themselves, EGFR-positive cells and processes were seen in close proximity to LHRH neurons and their nerve terminals, particularly in the area surrounding the lesion. Since TGF alpha gene expression is also increased in reactive astrocytes of POA-AHA lesions and blockade of EGFR prevented the advancing effect of the lesion on puberty (Junier et al., 1991b), the present results support the concept that, in lesioned animals, TGF alpha stimulates LHRH secretion indirectly via a paracrine mechanism that involves its interaction with EGFRs located on astroglial cells.

This article has been cited by other articles:

				B. M. Windsor-Engnell, E. Kasuya, M. Mizuno, K. L. Keen, and E. Terasawa An increase in in vivo release of LHRH and precocious puberty by posterior hypothalamic lesions in female rhesus monkeys (Macaca mulatta) Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1000 - E1009. [Abstract] [Full Text] [PDF]

				B. Liu, H. Chen, T. G. Johns, and A. H. Neufeld Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury. J. Neurosci., July 12, 2006; 26(28): 7532 - 7540. [Abstract] [Full Text] [PDF]

				B. Dziedzic, V. Prevot, A. Lomniczi, H. Jung, A. Cornea, and S. R. Ojeda Neuron-to-Glia Signaling Mediated by Excitatory Amino Acid Receptors Regulates ErbB Receptor Function in Astroglial Cells of the Neuroendocrine Brain J. Neurosci., February 1, 2003; 23(3): 915 - 926. [Abstract] [Full Text] [PDF]

				S. Boillee, J. Cadusseau, M. Coulpier, G. Grannec, and M.-P. Junier Transforming Growth Factor {alpha}: A Promoter of Motoneuron Survival of Potential Biological Relevance J. Neurosci., September 15, 2001; 21(18): 7079 - 7088. [Abstract] [Full Text] [PDF]

				Some Hypothalamic Hamartomas Contain Transforming Growth Factor {alpha}, a Puberty-Inducing Growth Factor, But Not Luteinizing Hormone-Releasing Hormone Neurons J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4695 - 4701. [Abstract] [Full Text]

				S. R. Ojeda, J. Hill, D. F. Hill, M. E. Costa, V. Tapia, A. Cornea, and Y. J. Ma The Oct-2 POU Domain Gene in the Neuroendocrine Brain: A Transcriptional Regulator of Mammalian Puberty Endocrinology, August 1, 1999; 140(8): 3774 - 3789. [Abstract] [Full Text]

				A. G. Rabchevsky, J. M. Weinitz, M. Coulpier, C. Fages, M. Tinel, and M.-P. Junier A Role for Transforming Growth Factor alpha  as an Inducer of Astrogliosis J. Neurosci., December 15, 1998; 18(24): 10541 - 10552. [Abstract] [Full Text] [PDF]

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