Hypothalamic growth hormone-releasing hormone (GHRH) deficiency: targeted ablation of GHRH neurons in mice using a viral ion channel transgene.
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 ((H37A)M2). In mammalian cells, (H37A)M2 forms a high conductance monovalent cation channel that can be blocked by the antiviral drug rimantadine. Transgenic mice with (H37A)M2 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 (H37A)M2 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 microg/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.
Le Tissier
Paul R
PR
Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
Carmignac
Danielle F
DF
Lilley
Sarah
S
Sesay
Abdul K
AK
Phelps
Carol J
CJ
Houston
Pamela
P
Mathers
Kathleen
K
Magoulas
Charalambos
C
Ogden
David
D
Robinson
Iain C A F
IC
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000172:deficiency*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010900:Pituitary Diseases / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000378:metabolism; D012299:Rimantadine / Q000494:pharmacology; D013997:Time Factors; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism
D000998:Antiviral Agents; D014763:Viral Matrix Proteins; D012299:Rimantadine; D013007:Growth Hormone-Releasing Hormone