Waite, EJ; (2007) Viral ion channel disruption of the somatotroph population in transgenic mice. Doctoral thesis , UCL (University College London).

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Abstract

Spontaneous and induced murine genetic models of disrupted somatotroph function have been useful in elucidating their relationships with other pituitary cell types as well as in studying downstream effects of GH deficiency. To disrupt somatotroph cell function in a temporally controlled fashion, I have applied a transgenic ion-channel conditional ablation strategy. The H37A variant of the influenza virus M2 protein that conducts monovalent cations unless blocked with the anti-influenza drug Rimantadine. This channel, previously shown to ablate GHRH neurons, has been targeted to somatotrophs using the hGH locus control region to attempt the conditional ablation of this cell population. Three fertile GH-M2 mouse lines have been generated with a growth phenotype and GH, IGF-1, PRL and TSH deficiencies that vary with copy number. Treatment of low and medium copy line male mice with GHRH and GHRP-6 suggests a greater effect on the low copy line than the hormone levels may indicate. It has not been possible to reverse the GH deficiency with Rimantadine treatment in vivo. A second model of drug-inducible somatotroph silencing using Ivermectin-sensitive chloride channels was therefore also investigated in preliminary studies. GH-M2 mice have been crossed with the GH-GFP and PRL-DsRed transgenic mouse lines to image the effect M2 expression has had on the GH and PRL cell networks with 2-photon microscopy. Analysis shows that the somatotroph network is disrupted, to varying degrees with age and GH deficiency, in GH-M2 mice. Unlike the GHRH-M2 pituitary, however, clusters are still observed. Counterstaining the blood vessels of a low copy line pituitary with rhodamine indicates that the majority of the remaining GH cells are in contact with the capillary system. The GH-M2 mice provide models for studies of the origin, maintenance and interrelationships of the pituitary cell types.

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