Regulatory and functional pathways mediating the control of central osmotic defences by hypothalamic transcription factor CREB3L1

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The bodily fluids of the mammalian organism are in a constant state of flux. Even in the absence of challenges such as dehydration, haemorrhage or starvation, salt and water are constantly being lost as a consequence of normal, obligatory renal excretory functions, and by the processes of respiration and perspiration. The body has two mechanisms that function to control the consumption and the excretion of water and salt, in order to maintain the optimal bodily content required for good health. The first mechanism involves the production, by a part of the brain called the hypothalamus, of a hormone called "arginine vasopressin" (AVP) that tells the kidney to conserve water. The second mechanism is behavioural, and involves the instincts of thirst and salt appetite that emotionally drive the organism to correct its fluid balance. These mechanisms can go wrong resulting in ill-health. For example, disorders of fluid balance are evident in a substantial proportion of elderly patients admitted to hospital, and dehydration is a frequent cause of morbidity and mortality in old people. AVP is a peptide hormone that is encoded by the corresponding AVP gene. When an animal becomes dehydrated, AVP is released from the hypothalamus and there is thus a need to make more. Twenty five years ago, we showed that the expression of the AVP gene is hence activated, and more messenger RNA (mRNA) is made from the gene, a process known as "transcription". It is the AVP mRNA that take the information coded by the gene to the cytoplasm of the cell. Here, the information in the mRNA is "translated" into protein. However, the exact molecular mechanisms involved have remained elusive, until now. Using methods that allow us to simultaneously describe the expression of all genes, we identified another gene, called CREB3L1, as being increased in expression in the hypothalamus following dehydration. CREB3L1 is a specialised protein (a "transcription factor") that controls the expression of target genes. We showed that CREB3L1 is expressed in AVP neurones, binds to the promoter region of the AVP gene, and hence drives its expression. Our aims are now to decipher the detailed molecular mechanisms by which CREB3L1 affects gene expression in the hypothalamus, and hence regulates the crucial hormonal processes that govern salt and water homeostasis. We will:*work out which signals tell the hypothalamus to increase the expression of CREB3L1 following dehydration.*find out what other proteins are bound to CREB3L1, which will tell us about upstream factors that regulate CREB3L1, and downstream effectors through which CREB3L1 might exerts its action. *find out what other genes in the AVP cell are regulated by CREB3L1. *determine how CREB3L1 globally affects the elaboration of neuropeptides in the hypothalamus. *embark upon studies that will tell us about the physiological roles of CREB3L1, the proteins that it interacts with and the genes that it regulates. Importantly, these experiments will take place in the physiological integrity of the whole organism. These unique studies will tell us about the mechanisms by which transcription factor protein affects gene expression in the brain, and hence mediates physiological stability.