Drosophila as a Model for Assessing the Function of RNA-Binding Proteins during Neurogenesis and Neurological Disease

Abstract

An outstanding question in developmental neurobiology is how RNA processing events contribute to the regulation of neurogenesis. RNA processing events are increasingly recognized as playing fundamental roles in regulating multiple developmental events during neurogenesis, from the asymmetric divisions of neural stem cells, to the generation of complex and diverse neurite morphologies. Indeed, both asymmetric cell division and neurite morphogenesis are often achieved by mechanisms that generate asymmetric protein distributions, including post-transcriptional gene regulatory mechanisms such as the transport of translationally silent messenger RNAs (mRNAs) and local translation of mRNAs within neurites. Additionally, defects in RNA splicing have emerged as a common theme in many neurodegenerative disorders, highlighting the importance of RNA processing in maintaining neuronal circuitry. RNA-binding proteins (RBPs) play an integral role in splicing and post-transcriptional gene regulation, and mutations in RBPs have been linked with multiple neurological disorders including autism, dementia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Fragile X syndrome (FXS), and X-linked intellectual disability disorder. Despite their widespread nature and roles in neurological disease, the molecular mechanisms and networks of regulated target RNAs have been defined for only a small number of specific RBPs. This review aims to highlight recent studies in Drosophila that have advanced our knowledge of how RBP dysfunction contributes to neurological disease.

RNA-recognition motif in Matrin-3 mediates neurodegeneration through interaction with hnRNPM

“…Drosophila is a versatile model system that has been used for over a century to study the molecular mechanisms of key biological functions given their genetic and overall experimental tractability [ 41 ]. In the context of ALS, Drosophila has been extensively used to model both genetic (mutations in ALS-associated genes) and environmental insults (traumatic brain injury) that lead to disease pathogenesis [ 42 – 45 ].…”

Drosophila mRNA Localization During Later Development: Past, Present, and Future

“…The localization of mRNAs is essential for the proper axon guidance, formation and remodeling of dendrites to form neural circuits throughout development, as discussed above. The proper localization of mRNAs are also required for memory and learning in both flies and humans (reviewed in Greenspan, 2003 ; Agnès and Perron, 2004 ; Puthanveettil, 2013 ; Olesnicky and Wright, 2018 ). However, genetic screens in flies are starting to identify additional functional roles for proteins that likely have a role in mRNA localization (for example Song et al, 2007 ; Martin and Ephrussi, 2009 ; Hayashi et al, 2014 ; Misra et al, 2016 ).…”

Analysis of pre-symptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration

“…Highlighting the conservation of protein functions from fly to human, expression of human FUS and TDP-43 proteins was shown to rescue the lethality induced upon inactivation of the corresponding fly genes (Wang et al 2011). Furthermore, Drosophila models based on expression of mutant human or Drosophila proteins that recapitulate the hallmarks of SMA and ALS, in particular motor neuron disabilities and degeneration, have been previously established (McGurk et al 2015; Aquilina and Cauchi 2018; Olesnicky and Wright 2018; Spring et al 2019; Liguori et al 2021). Several of these models have been successfully used for large-scale screening and discovery of genetic modifiers (Chang et al 2008; Kankel et al 2020; Liguori et al 2021).…”