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. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

Keywords: RNA binding protein; alternative polyadenylation; alternative splicing; neurodevelopment; neuronal health.

Figure 1.. Neuronal development and the formation of neuronal circuits

(A) Schematic of cortical neuron development. Neuronal progenitors in the ventricular and subventricular zones (VZ and SVZ, respectively), undergo a multi-polar to bi-polar transition, then migrate outward through the intermediate zone (IZ) along radial glia to form the layers of the cerebral cortex. (B) Schematic of a synapse. Vesicles containing neurotransmitters are released from the pre-synaptic neuron into the synaptic cleft, where ligand-gated ion channel receptors on the post-synaptic neuron receive and transmit electrical signals. (C) Synaptic connections are established via homophilic interactions of adhesion molecules expressed on the cell surface (left; blue/purple/pink, cell adhesion molecules), secretion of chemoattractants or chemorepellents to guide localized synapse formation (middle), and via neuronal activity stimulated via neurotransmitter release into the chemical microenvironment (right).

Figure 2.. Alternative mRNA processing generates isoform diversity.

Each row represents a type of alternative transcript processing. Splice junctions demonstrate inclusion or exclusion of transcript exons/regions (red/purple, alternative inclusion/extension) compared to constitutive exons/regions (black).

Figure 3.. Alternative mRNA processing in neurons alters several transcript features.

mRNA processing in neurons is highly regulated and controls several transcript features, including subcellular localization, stability/decay, miRNA-mediated regulation, local translation, protein function, and RNA binding protein (RBP) recruitment.