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Characterization of the potential role of Luman as a novel regulator of animal stress responses

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Title: Characterization of the potential role of Luman as a novel regulator of animal stress responses
Author: Penney, Jenna
Program: Molecular and Cellular Biology
Advisor: Lu, Ray
Abstract: This thesis is an investigation of a knockout (KO) mouse line of Luman/CREB3. Luman KO mice are viable and survive into adulthood, however, the Mendelian distribution is skewed, in that less than 5% of pups born from heterozygous (het) breeding pairs expressed the KO genotype. The Luman-deficient mice are smaller in size, have less visceral fat, low fertility and exhibit a maternal defect, characterized by a low rate of pup survival. Through further characterization of the mice I determined that when Luman is deficient, the mice exhibit a blunted stress response, characterized by low levels of both anxiety and depressive-like behaviour, in addition to low glucocorticoid (GC) levels and increased glucocorticoid receptor (GR) expression. Resulting from the change in GC/GR levels, LUMAN alters the GR response leading to an increase in activity and dysregulation in the central stress response system, the hypothalamic pituitary adrenal (HPA) axis. These observations lead me to two hypotheses: (1) deficiency of LUMAN increases GR expression, resulting in increased negative feedback in the HPA axis, leading to low GC secretion, and (2) when LUMAN is deficient the secretion of GCs is insufficient leading to a compensatory increase in GR during development which persists through life. While these possibilities are not mutually exclusive I designed experiments to dissect the mechanism of action. I have shown that LUMAN binds to GR through the LxxLL motif, and through this interaction activates GR in the absence of ligand. Once activated, LUMAN binds to the promoter region of genes containing glucocorticoid response elements (GREs) through the DNA binding domain (DBD), increasing the activity of GR. These results suggest that LUMAN alters GR expression, through acting as a transcription factor and a cofactor. On the other hand, in the absence of LUMAN basal secretion levels are not altered, however, the cells are more sensitive to cellular stress when LUMAN is absent. These data suggest that both mechanisms may play a part in how LUMAN regulates GR. I postulate that LUMAN alters HPA axis reactivity through increasing GR expression and decreasing GC secretion, leading to a blunted response to stress.
Date: 2017-08-22

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