Investigating the novel neurogenic mTOR pathway component Unkempt in Drosophila

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

A fundamental challenge during development is the correct proliferation and differentiation of neuronal stem cells to produce a fully functional nervous system. One important regulator of this process is the mechanistic target of rapamycin (mTOR) signalling pathway. The mTOR kinase integrates signals from mitogens, nutrients and energy levels to regulate growth, metabolism and also neurogenesis. Loss of precise temporal control caused by mutations in mTOR pathway components can lead to neurodevelopmental disorders such as epilepsy and autism. The mechanisms, however, by which mTOR regulates neurogenesis, are not known. In this thesis, I aim to investigate the novel neurogenic regulator Unkempt and its role downstream of mTOR signalling. Unkempt is a zinc finger and RING domain protein that has been shown to regulate neuronal cell morphology in the mammalian cortex and the differentiation of photoreceptor neurons in Drosophila. I was able to demonstrate that Unkempt, as well as its binding partner Headcase, are expressed throughout the Drosophila central nervous system. Loss of Unkempt in neuronal stem cells causes an increase in neuronal progeny. Additionally, neurons lose their temporal identity, which is manifested in a temporal transition defect from early to late born neurons. Over-activation of mTOR signalling in neuronal stem cells through the loss of TSC1, manifests itself in a similar neurogenic phenotype. Using structure function analysis, I have identified the Unkempt zinc finger domain to be essential for protein-protein interactions with Headcase and necessary for its function in vivo. Summarizing, Unkempt is a novel regulator of neurogenesis in the Drosophila central nervous system acting downstream of mTOR to control the temporal transition from early to late born neurons.
Date of Award1 Jul 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJoseph Bateman (Supervisor), Giovanna Lalli (Supervisor) & Rita Sousa-Nunes (Supervisor)

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