RNA and neuronal function: the importance of post-transcriptional regulation

Abstract

The brain represents an organ with a particularly high diversity of genes that undergo post-transcriptional gene regulation through multiple mechanisms that affect RNA metabolism and, consequently, brain function. This vast regulatory process in the brain allows for a tight spatiotemporal control over protein expression, a necessary factor due to the unique morphologies of neurons. The numerous mechanisms of post-transcriptional regulation or translational control of gene expression in the brain include alternative splicing, RNA editing, mRNA stability and transport. A large number of trans-elements such as RNA-binding proteins and micro RNAs bind to specific cis-elements on transcripts to dictate the fate of mRNAs including its stability, localization, activation and degradation. Several trans-elements are exemplary regulators of translation, employing multiple cofactors and regulatory machinery so as to influence mRNA fate. Networks of regulatory trans-elements exert control over key neuronal processes such as neurogenesis, synaptic transmission and plasticity. Perturbations in these networks may directly or indirectly cause neuropsychiatric and neurodegenerative disorders. We will be reviewing multiple mechanisms of gene regulation by trans-elements occurring specifically in neurons.

Keywords: RNA editing and neuronal granules; alternative splicing.

Figure 1

Illustration depicting key post-transcriptional events and trans-elements involved in involved in PTR in neurons.

Figure 2

(a) Neuron specific splicing patterns of PTB and nPTB. In non-neuronal cells, PTB mRNA undergoes normal translation forming functional PTB that in turn binds to nPTB mRNA leading to exon skipping and NMD. Also, PTB binds to its own mRNA in a concentration dependent manner, resulting in NMD, thus ensuring homeostasis. However, in neuronal cells, miR-124 is expressed that binds to the PTB mRNA leading to translational suppression. Lower concentration of PTB restricts its binding to nPTB mRNA (adapted from [43, 96]). (b) Similar to nPTB, PTB mediates the AS pattern of ERC mRNA. Presence of PTB in non-neuronal cells leads to exon exclusion in ERC mRNA leading to synthesis of ERC1a isoform, whereas in non-neuronal cells, ERC1b isoform is expressed, which contains an additional exon (adapted from [26]). (c) RbFox determines the splicing pattern of AnkG mRNA. Knockout of RbFox leads to exon inclusion in AnkG resulting in a mutant protein that impairs assembly of the AIS (adapted from [104]). (d) RbFox with hnRNP M and other regulators forms the large macromolecular assembly of splicing regulator complex that acts constitutively based on the presence of corresponding binding sites and is involved in changes in splicing patterns (adapted from [46]).

Figure 3

(a) ADAR mediated RNA editing. ADAR mediates the conversion of A-to-I in mRNAs and factors like Zn72D and FMRP regulates this process (adapted from [17, 187, 218]). (b) Translational control of Vamp1 mRNA. Rbfox and miR-9 competitively approach the binding site in the 3′-UTR of Vamp1 mRNA. Binding of Rbfox enhances the mRNA stability and aids translation, whereas binding of miR-9 represses translation of Vamp1 (adapted from [222]).

Figure 4

Role of BACE1-AS lncRNA in driving APP aggregation. BACE1 is an enzyme that cleaves APP aberrantly and drives aggregation. Under normal conditions, BACE1 expression is lower due to miRNA (miR-485-5p) mediated degradation of bace1 mRNA. However, during stress the expression of BACE1-AS is upregulated. BACE1-AS competes for the same site as miR-485-5p and successful binding of the lncRNA confers stability to bace1 mRNA and promotes translation. This image is based on work presented in [68, 69].

Figure 5

(a) Localization of GAP-43 mRNA in axons. Binding of Hud and Zbp1 to the ARE element in the 3′-UTR of GAP-43 transports the mRNA to axons (adapted from [246]). (b) Localization of BDNF mRNA in dendrites. Based on the length of BDNF mRNA 3′-UTR, the factors required for dendritic localization vary. CPEB-1, CPEB-2, ELAV-2 and ELAV-4 are crucial for the dendritic localization of BDNF mRNA with short 3′-UTR, whereas CPEB1, ELAV1, ELAV3, ELAV4, FMRP and FXRP2 are required for the localization of BDNF mRNA with long 3′-UTR (adapted from data presented in [220]). (c) Formation of neuronal granules. Neuronal granules, which are transported from the soma to the nerve ending, are formed by non-covalent interaction between mRNAs and RBPs (adapted from [74]).