Emerging Roles of RNA-Binding Proteins in Neurodevelopment

Abstract

Diverse cell types in the central nervous system (CNS) are generated by a relatively small pool of neural stem cells during early development. Spatial and temporal regulation of stem cell behavior relies on precise coordination of gene expression. Well-studied mechanisms include hormone signaling, transcription factor activity, and chromatin remodeling processes. Much less is known about downstream RNA-dependent mechanisms including posttranscriptional regulation, nuclear export, alternative splicing, and transcript stability. These important functions are carried out by RNA-binding proteins (RBPs). Recent work has begun to explore how RBPs contribute to stem cell function and homeostasis, including their role in metabolism, transport, epigenetic regulation, and turnover of target transcripts. Additional layers of complexity are provided by the different target recognition mechanisms of each RBP as well as the posttranslational modifications of the RBPs themselves that alter function. Altogether, these functions allow RBPs to influence various aspects of RNA metabolism to regulate numerous cellular processes. Here we compile advances in RNA biology that have added to our still limited understanding of the role of RBPs in neurodevelopment.

Endogenous neural stem cells characterization using omics approaches: Current knowledge in health and disease

“…RNA binding proteins (RNABP) represent critical controllers of development (Parra and Johnston, 2022 ). The RNABP Quaking 5 (Qki5) has been found to decrease in neuronal progenitors and shown to regulate the transcription of cell adhesion molecule genes via binding to the intronic RNA (Hayakawa-Yano et al, 2017 ).…”

The HNRNPF/H RNA binding proteins and disease

“…In contrast, lower levels of HNRNPH expression results in an accumulation of the TRF2‐S isoform and sequestration of REST in the cytoplasm and the de‐repression of neuronal genes silenced by REST and neuronal differentiation (Grammatikakis et al, 2016). Given these types of observations, it is unsurprising that deregulated RBP function is the underlying cause of several neurodevelopmental disorders (LaForce et al, 2022; Parra & Johnston, 2022; Prashad & Gopal, 2021), including Fragile X syndrome (FXS), which develops because of disrupted expression of the fragile X mental retardation protein (FMRP), a regulator of mRNA translation, RNA stability and subcellular localization (Protic et al, 2022). Added to this list in recent years are reports of neurodevelopmental disease‐associated sequence changes in genes encoding hnRNPs, including the HNRNPF/H genes.…”

Adaptation of RiPCA for the Live-Cell Detection of mRNA-Protein Interactions

“…8 Considering the significance of mRNA-protein interactions in ensuring maintenance of cellular homeostasis, dysregulation of this networking contributes to the development of several human diseases including cancers, neurodegenerative, cardiovascular, and autoimmune diseases. [9][10][11][12][13][14] Accordingly, the targeting of RNA-protein interactions (RPIs) with small molecules has emerged as a new area of RNA-targeted drug discovery. 15,16 To enable these efforts, our laboratory has worked to develop cell-based assay technology for detecting RPIs, RNA-Interaction with Protein-mediated Complementation Assay (RiPCA) (Figure 2).…”