mRNA isoform balance in neuronal development and disease

Abstract

Balanced mRNA isoform diversity and abundance are spatially and temporally regulated throughout cellular differentiation. The proportion of expressed isoforms contributes to cell type specification and determines key properties of the differentiated cells. Neurons are unique cell types with intricate developmental programs, characteristic cellular morphologies, and electrophysiological potential. Neuron-specific gene expression programs establish these distinctive cellular characteristics and drive diversity among neuronal subtypes. Genes with neuron-specific alternative processing are enriched in key neuronal functions, including synaptic proteins, adhesion molecules, and scaffold proteins. Despite the similarity of neuronal gene expression programs, each neuronal subclass can be distinguished by unique alternative mRNA processing events. Alternative processing of developmentally important transcripts alters coding and regulatory information, including interaction domains, transcript stability, subcellular localization, and targeting by RNA binding proteins. Fine-tuning of mRNA processing is essential for neuronal activity and maintenance. Thus, the focus of neuronal RNA biology research is to dissect the transcriptomic mechanisms that underlie neuronal homeostasis, and consequently, predispose neuronal subtypes to disease.

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.…”

KIS counteracts PTBP2 and regulates alternative exon usage in neurons

“…Moreover, AS is known to drive many aspects of neurogenesis, including neural progenitor cell proliferation and differentiation, axon guidance, synapse formation, and synaptic plasticity ( Vuong et al, 2016b ; Furlanis and Scheiffele, 2018 ). The relevance of AS as a regulatory mechanism is evidenced by numerous examples in which alterations in splicing are associated with pathological states ( Gandal et al, 2018 ; LaForce et al, 2023 ; Schieweck et al, 2021 ). Although fine-tuning mRNA processing is essential for neuronal activity and maintenance, insights into its regulation are just starting to emerge.…”

Sites of transcription initiation drive mRNA isoform selection

“…Alternative 3′ UTRs, through distinct sequence and structure elements that dictate interactions of the transcript with microRNAs and RNA-binding proteins (RBPs), regulate the encoded protein’s abundance, localization, and integration into protein complexes. 1 APA modulates protein function in a context-specific, gene-specific, or cell-type-specific manner and is critically involved in a variety of cellular processes; indeed, numerous human diseases including cancer and neurological disorders 2 , 3 are associated with APA deregulation. 3′ UTR genetic variants contribute to a substantial number of phenotypic traits and disease heritability, 4 , 5 making APA a possible actionable target for therapeutic intervention.…”