Mef2c in the development of the striatum

Quinn, David 2020. Mef2c in the development of the striatum. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Understanding the process of normal striatal differentiation is important for gaining insight into diseases affecting this area of the brain, ranging from addiction to neurodegenerative conditions such as Huntington’s disease (HD). An Affymetrix screen of mouse striatal development revealed Mef2c to be significantly up-regulated suggesting that could plays a role in striatal development. Recent research has shown that the KO of Mef2c impaired neuronal differentiation and maturation, affected hippocampal based learning and memory and directly influenced neuronal development including dendrite morphogenesis and spine density. Then aim of this investigation was to determine what, if any, role Mef2c holds in the development of the mouse striatum. Chapter 3 established Mef2cloxP/loxP mice as a WT control and that heterozygous mice were not significantly different to WT, therefore necessitating the use of a conditional KO model. LacZ and protein expression analysis revealed that Gsx2-Cre is expressed throughout the striatum at both P7 and 3 months, appearing to dramatically reduce the numbers of MEF2C positive MSNs, thus is suitable to serve as the KO model Chapter 4 demonstrated that Conditional KO of Mef2c results in fewer Darrp-32 expressing cells at P7, a total cell count reduction at 3 months (most severely with Foxp1 and Darrp-32), with FOXP1 and DARPP-32 counts remaining lower at 12 and 18 months. The conditional KO striatal volume is reduced in all adult ages, but not at P7. Substantial neurogenesis occurs in the P14 striatum but is significantly reduced following loss of MEF2C expression, with both proliferation in both genotypes reduced by P24, suggesting that MEF2C lowers total cell counts in adult mice by hindering striatal cell proliferation. Loss of MEF2C is results in an increase in spine densities and counts in adult mice, but does not affect dendrites. Chapter 5 demonstrated loss of Mef2c has a range of significant effects on cells isolated from the developing E18 striatum and analysed in vitro, altering the cellular composition of striatal culture populations both immediately after plate down and following several days of cultures. Mef2c expression is required for normal proliferative activity, apoptotic activity and the in vitro differentiation of MSNs.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	9 September 2020
Last Modified:	09 Sep 2021 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/134751

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