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Molecular Endocrinology, doi:10.1210/me.2004-0223
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Molecular Endocrinology 19 (5): 1251-1262
Copyright © 2005 by The Endocrine Society

Hypothalamic Growth Hormone-Releasing Hormone (GHRH) Deficiency: Targeted Ablation of GHRH Neurons in Mice Using a Viral Ion Channel Transgene

Paul R. Le Tissier, Danielle F. Carmignac, Sarah Lilley, Abdul K. Sesay, Carol J. Phelps, Pamela Houston, Kathleen Mathers, Charalambos Magoulas, David Ogden and Iain C. A. F. Robinson

National Institute for Medical Research, Divisions of Molecular Neuroendocrinology (P.L.T., D.F.C., P.H., C.M., I.C.A.F.), Neurophysiology (S.L., A.K.S., D.O.), and Biological Services (K.M.), The Ridgeway, London NW7 1AA, United Kingdom; and Department of Structural and Cellular Biology (C.J.P.), Tulane University School of Medicine, New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Professor Iain C. A. F. Robinson, Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. E-mail: irobins{at}nimr.mrc.ac.uk.

Animal and clinical models of 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 that can be blocked by the antiviral drug rimantadine. Transgenic mice with H37AM2 expression targeted to GHRH neurons developed postweaning 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, although GH cells were still present. GHRH-M2 mice were also deficient in prolactin but not TSH. 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 (100 µg/d) for 7 d 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 prolactin production and normal growth.




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