Unravelling a novel role for the mineralocorticoid receptor in dentate gyrus neurogenesis

Abstract

The mineralocorticoid receptor (MR) is one of two corticosteroid receptors that bind glucocorticoid hormones which are secreted into the blood following stress or circadian variations. MR activation influences cellular and molecular processes such as adult neurogenesis. Adult neurogenesis occurs in restricted brain regions, including the dentate gyrus of the hippocampus, an area showing a high expression of MR. Recent publications identified a role for MR in the regulation of neuronal differentiation and maturation. These studies also suggested that MR has a regulatory role on ciliary processes through associations with the genome at X-box motifs, where the transcription factor RFX3 can also bind. However, to date, there have been few investigations into the underlying mechanisms
of this regulation. In this thesis, we uncovered the requirement of MR activation in neuronal differentiation and ciliogenesis in human foetal neural progenitor cells. Subsequently, investigations into MR expression in the adult rat dentate gyrus found that its expression follows the developmental timeline of neurogenesis, with highest expression in mature neurons and no expression in progenitor cells. Furthermore, we found a high degree of co-localisation between MR and RFX3, suggesting RFX3 may have a regulatory role in neurogenesis. To investigate these regulatory mechanisms, we conducted RFX3 ChIP-sequencing to ascertain its genomic binding profile and hippocampal functions. Simultaneously, we utilised sequencing data to explore the epigenetic landscape of the Nr3c2 gene to identify putative mechanisms for its induction during neurogenesis. Subsequent pCREB ChIP-sequencing studies under baseline and acute stress conditions showed that, in addition to pCREB, there may be other potential co-regulators of MR, and thus possibly the process of neurogenesis. Overall, we have uncovered putative transcription factors involved in MR induction as part of neuronal differentiation and ciliogenesis. This work provides novel insights that future research can expand on to elucidate mechanisms underlying MR’s regulation of neurogenesis.

Date of Award	7 May 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	J M H M Reul (Supervisor), Oscar Cordero Llana (Supervisor) & Karen R Mifsud (Supervisor)