Eccleston, Lynne Marie; (1990) Expression and hormonal regulation of the growth hormone releasing factor gene. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neuropeptide messenger RNAs are generally of relatively low abundance and often have a very limited tissue distribution, being present in a defined and limited subset of neurones. This makes the study of their regulation by conventional RNA hybridisation techniques very difficult, and thus the technique of in situ hybridisation histochemistry has been used to localise growth hormone releasing factor (GRF) mRNA to cell bodies within the mediobasal hypothalamus. The gene is primarily expressed in cell bodies within the arcuate nucleus and around the ventromedial hypothalamus (VMH). This is in agreement with immunocytochemical studies, which have shown the presence of the peptide in a similar set of neurones. The method of in situ hybridisation has been verified and optimised to provide an objective and quantitative means of investigating changes in mRNA content which may result from hormonal or surgical manipulations. After hypophysectomy, GRF mRNA levels are increased by 3-5 fold in the hypothalamus by two separate mechanisms. In the arcuate nucleus the amount of mRNA per cell is increased by 70% in hypophysectomised animals when compared to controls. Additionally, there is an 80% increase in the number of cells expressing the GRF gene around the VMH. Both growth hormone (GH) and thyroxine (T4) replacement partially attenuate these increases. GH and T4 may act synergistically. In a parallel study carried out on hypothyroid rats, there was no significant change in GRF mRNA levels; however, these animals may still be secreting some GH. These results demonstrate the feedback loop that exists between GH and the GRF neurones, although thyroid hormones and glucocorticoids may also be involved. The additional cells expressing the GRF mRNA after hypophysectomy may demonstrate the plasticity of the adult CNS, where these cells are recruited to express the GRF gene by the endocrine environment. Extra-hypothalamic sites of synthesis of GRF have been addressed using in situ hybridisation, in the GI tract and reproductive system. GRF mRNA has been found in submucosal Brunner's glands in the duodenum, and within Sertoli cells in the testis.

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