Investigating DDX6 and its potential role in miRNA-mediated gene silencing events in neurones.

Student thesis: Master's ThesisMaster of Science by Research (MScR)

Abstract

Micro-RNAs (miRNAs) are short non-coding RNAs that modulate gene expression at the post- transcriptional level. This is achieved through associations with Argonaute (Ago), a protein within the RNA-induced silencing complex (RISC). Specific miRNAs are required for NMDAR- dependent synaptic plasticity, through tight regulation of proteins involved in dendritic spine morphology, such as Limk1. NMDAR-dependent suppression of Limk1 via miR-134 is vital for dendritic spine shrinkage and requires phosphorylation of Ago2 at S387. NMDAR-dependent S387 phosphorylation also increases Ago2:DDX6 interactions. Dead box protein DDX6 is an
RNA helicase that has been implicated in RISC function and RNA interference processes, though a specific role for DDX6 in neuronal gene silencing has yet to be established. In the context of progenitor cell differentiation and viral pathogenicity, DDX6 has been shown to preferentially associate with specific mRNAs through various secondary structures present within their 3’UTR. DDX6 helicase activity has the potential to modulate miRNA-dependent silencing, based on the regulatory action it has on secondary structures within the 3’UTR of mRNAs. It is unclear if the helicase activity of DDX6 shows specificity toward the miRNAs to which it preferentially binds. Here I provide tentative evidence that knockdown of DDX6
blocks the NMDAR-dependent decrease of Limk1, regulated via miR-134, whilst knockdown of DDX6 has no effect on NMDAR-dependent repression of Apt1, regulated by miR-138. This work suggests that DDX6 could show specificity during RNA interference processes and highlights this mechanism as an avenue for further investigation.
Date of Award18 Jun 2024
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorJonathan G Hanley (Supervisor)

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