Nervous translation, do you get the message? A review of mRNPs, mRNA-protein interactions and translational control within cells of the nervous system

Abstract

In neurons, translation of a message RNA can occur metres away from its transcriptional origin and in normal cells this is orchestrated with perfection. The life of an mRNA will see it pass through multiple steps of processing in the nucleus and the cytoplasm before it reaches its final destination. Processing of mRNA is determined by a myriad of RNA-binding proteins in multi-protein complexes called messenger ribonucleoproteins; however, incorrect processing and delivery of mRNA can cause several human neurological disorders. This review takes us through the life of mRNA from the nucleus to its point of translation in the cytoplasm. The review looks at the various cis and trans factors that act on the mRNA and discusses their roles in different cells of the nervous system and human disorders.

Fig. 1

Stau2 mediated nucleocytoplasmic shuttling. A schematic representation of a neuron showing the two proposed mechanisms in which Stau2 may be invovled in export of RNA from the nucleus to the cytoplasm. In the Exp5-dependent pathway, an RNA containing a minihelix acts as an adapter to link Stau2 and Exp5 and the complex is exported. In the Crm1-mediated pathway a separate pool of RNA, that do not bind Exp5, are bound by Stau2 and exported to the cytoplasm. Both pathways use the hydrolysis of GTP by Ran for export, subsequently Stau2-RNA complex is incorporated into an RNA granule for transport along the dendrite (adapted from [47])

Fig. 2

A2RE mediated nucleocytoplasmic shuttling. A2RE-containing RNA and its cognate trans-acting factor, hnRNP A2, are exported from the nucleus to the cytoplasm as a complex. The latter cycles between the cytoplasm and the nucleus. The carriers transportin 1 (trn) and NTF2 shuffle cargo or Ran molecules through the nuclear pore. The ratio of RanGTP to RanGDP determines the direction of cargo movement. RCC1, the regulator of chromosome condensation 1, binds to the nuclear GTP-binding protein, Ran. This figure is reproduced here with the kind permission of Prof. John Carson, Prof. Elisa Barbarese, and Portland Press

Fig. 3

HuD, KIF3A and tau mRNA colocalise in RNP granules. a Phase image: the growth cone is shown on the right side of the panel. Colocalisation of tau mRNA (b, red), HuD protein (c, green) and KIF3A (d, cyan) to yield the merged image presented in e of the axon and growth cone of differentiated P19 cells. The curved arrowhead denotes colocalisation of the three components (white). The asterisk denotes colocalisation of HuD and KIF (light green). The straight arrowhead denotes colocalisation of HuD and tau mRNA (yellow). Bar 1 mm (′40,000 magnification). Reproduced with permission of the Company of Biologists from [65]

Fig. 4

Derepression of Translation. Repression of translation is shown in the upper panel in which unphosphorylated cytoplasmic polyadenylation element-binding protein (CPEB) is depicted in a complex bound to its recognition sequence (CPE) and maskin. In this configuration eukaryotic translation initiation factor 4E (eIF4E),which interacts with the 5′ 7-methyl-GTP cap (m⁷G) is unable to interact with eIF4G. Upon stimulation, CPEB is phosphorylated (lower panel). Derepression of translation occurs when phosphorylated CPEB interacts with cytoplasmic polyadenylation specificity factor (CPSF) which allows poly(A) polymerase (PAP) to extend the polyadenylated tail and recruits poly(A) binding protein (PABP). These changes allow PABP to bind eIF4G through the release of the eIF4E-Masking interaction allowing translation of the open reading frame (ORF). Adapted from [180]

Fig. 5

The continuum of mRNPs. The difference between neuronal mRNP and stress granules is dynamic with shared components making the core mRNP, proteins are added and subtracted from the complexes to respond to cellular demands and function. In this model it may not be possible to define the differences between an mRNP and Stress granules or other RNA-protein complexes

Fig. 6

Colocalization of endogenous SMN and Gemin proteins in neurites and growth cones in primary forebrain culture and ES cell-derived motor neurons. a SMN (red) and Gemin2 (green) in cultured forebrain neurons (3 DIV) were detected by double-labelled immunofluorescence using a monoclonal antibody to SMN and polyclonal antibody to Gemin2. The nucleus was stained with DAPI (blue). Higher magnification of two regions (insets 1, 2 from top panel are enlarged in bottom panel) depicts the frequent colocalization between SMN and Gemin2 within granules in the growth cone (1, arrows) and neurite (2, arrows). b Double-labelled IF showing colocalization of SMN (red) and Gemin2 (Cy5 antibody displayed in green) in neurites of ES cell-derived differentiated motoneuron. Higher magnification of a boxed region depicts numerous granules with colocalization between SMN and Gemin2 (bottom panel, arrows). c These cells express EGFP from a motor neuron-specific promoter. d IF detection of Gemin3 with a monoclonal antibody depicts many granules localised to the EGFP-positive axon and growth cone of the motor neuron (arrows). Reproduced with permission of the Journal of Neuroscience from [168]