Wells, Sara Elizabeth; (1997) The expression of neuroendocrine genes in transgenic rats. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of the project described in this thesis was to generate transgenic rats targetting neuroendocrine systems, with particular reference to the hormones vasopressin (AVP), oxytocin (OT) and growth hormone (GH). The use of rats in preference to mice was guided by the extensive background of research done into their neuroendocrine systems as they are large enough to be physiologically manipulated. A rat cosmid library was screened to isolate large fragments of DNA including the whole of the rat OT/AVP locus and flanking sequences. These cosmids were used to engineer a construct spanning 44kb of this locus with bovine oxytocin-neurophysin (bNP) and human GH (hGH) as reporter genes respectively. Using this construct, two lines of transgenic rats have been generated in which the cell-specific expression of the transgenes has been investigated. The hGH transgene is expressed specifically in magnocellular neurones in the hypothalamus of both lines as verified by immunocytochemistry, radioimmunoassay and RT-PCR. Physiological stimuli and a whole animal antidiuretic bioassay have been used to manipulate the endogenous AVP system and therefore the transgene levels in these rats to investigate whether hGH is being regulated appropriately. The male rats of one of the lines of transgenics are subfertile and become obese in adulthood. They also have a reduction in endogenous growth hormone (rGH) and prolactin. This phenotype has been explored and compared with another transgenic rat model where the hGH transgene is targetted to the hypothalamic neurones which control rGH levels resulting in a dominant dwarfism phenotype. This has allowed an insight into the effects of this transgene when targetted to different neuroendocrine system. The bNP transgene, however, does not have detectable expression in these transgenic rats.

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