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Submitted on June 1, 2004
Accepted on January 11, 2005
National Institute for Medical Research, Divisions of Molecular Neuroendocrinology, Neurophysiology, and Biological Services, The Ridgeway, London NW7 1AA, UK, and Department of Structural & Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112-2699, USA
* To whom correspondence should be addressed. E-mail: irobins{at}nimr.mrc.ac.uk.
Animal and clinical models of growth hormone releasing hormone (GHRH) excess suggest that GHRH provides an important trophic drive to pituitary somatotrophs. We have adopted a novel approach to silence or ablate GHRH neurons, using a modified H37A variant of the influenza virus M2 protein (H37AM2). In mammalian cells, H37AM2 forms a high conductance monovalent cation channel which can be blocked by the anti-viral drug rimantadine. Transgenic mice with H37AM2 expression targeted to GHRH neurons developed post-weaning dwarfism with hypothalamic GHRH transcripts detectable by rt-PCR but not by in situ hybridization and immunocytochemistry, suggesting that expression of H37AM2 had silenced or ablated virtually all the GHRH cells. GHRH-M2 mice showed marked anterior pituitary hypoplasia with GH deficiency, though GH cells were still present. GHRH-M2 mice were also deficient in PRL but not thyrotropin. Acute iv injections of GHRH in GHRH-M2 mice elicited a significant GH response, whereas injections of GHRP-6 did not. Twice daily injections of GHRH (100µg/day) for 7 days in GHRH-M2 mice doubled their pituitary GH but not PRL contents. Rimantadine treatment failed to restore growth or pituitary GH contents. Our results show the importance of GHRH neurons for GH and PRL production and normal growth.
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