Mef2c transcription factor is required for the development of medium spiny neurons of the mouse striatum

Ali, Heba 2022. Mef2c transcription factor is required for the development of medium spiny neurons of the mouse striatum. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Medium spiny neurons (MSNs) are the major projection of the striatum and are the neurons predominantly degenerating in Huntington’s disease. Understanding normal striatal MSNs development is important for several areas of applied research; it is key in understanding the pathological conditions affecting this area of mouse brain, and for improving protocols for differentiating MSNs from pluripotent stem cells for use as cell models of disease or for generating cells for cell-based therapy of neurodegenerative diseases like HD. We have shown the transcription factor Mef2c to be significantly upregulated in the striatum over a period encompassing peak generation of medium spiny neurons (MSNs). Here I present data that suggest a significant functional role of Mef2c in the survival of MSNs in the mouse striatum The spatiotemporal expression of Mef2c in embryonic and postnatal mouse striatum was determined, Mef2c was found to be expressed predominantly in MSNs of the striatal matrix compartment. To investigate the role of Mef2c in MSNs development, a striatal-specific Cre mouse line was used to knockout Mef2c in the mouse striatum (CKO) during embryonic development. The histological effects on mouse striatum were assessed in a developmental series between P2 and 12 months, which showed a significant reduction in striatal volume and MSNs count in CKO striatum at P14 onward and a mild, yet significant effect on dendritic spine development. Behavioral testing of 12-month-old CKO mice showed a significant impairment in motor functions and in the exploratory behavior of new environments, demonstrating the functional importance of Mef2c in MSN development. The mechanism underlying the loss of MSNs was explored and a significant increase in poptotic activity was observed in P3 CKO striatum, with more apoptotic cells in matrix compartment. This was accompanied with a significant reduction in the anti-apoptotic factor Bcl-xl. Suggest that Mef2c loss impacted MSNs survival in matrix compartment through altering Bcl-xl mediated pathways. In conclusion, this thesis investigated the functional role of Mef2c in the development of mouse striatum through studying a striatal specific CKO mouse model and showed that Mef2c is required for the survival of a subpopulation of matrix MSNs

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Last Modified:	25 Oct 2023 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/153775

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