Non coding RNA and brain

Abstract

Small non coding RNAs are a group of very different RNA molecules, present in virtually all cells, with a wide spectrum of regulatory functions which include RNA modification and regulation of protein synthesis. They have been isolated and characterized in all organisms and tissues, from Archaeobacteria to mammals. In mammalian brain there are a number of these small molecules, which are involved in neuronal differentiation as well as, possibly, in learning and memory. In this manuscript, we analyze the present knowledge about the function of the most important groups of small non-coding RNA present in brain: small nucleolar RNAs, small cytoplasmic RNAs, and microRNAs. The last ones, in particular, appear to be critical for dictating neuronal cell identity during development and to play an important role in neurite growth, synaptic development and neuronal plasticity.

Figure 1

Schematic secondary structure of the two classes of snoRNAs. A) H/ACA box snoRNAs fold into "hairpin-hinge-hairpin-tail" structures and contain two short sequences called boxes H and ACA, as indicated in the white boxes. The hairpins are interrupted by an internal loop that forms the pseudouridylation pocket. A set of conserved proteins, Nhp2, Gar1, Cbf5 and Nop10, recognize and bind to this structure. B) C/D box snoRNAs show conserved boxes termed C (UGAUGA) and D (CUGA), positioned near their 5' and 3' termini. Sometimes two additional, less conserved, boxes called C' and D' are present. C and D boxes form a characteristic secondary structure: the K-turn motif. Four evolutionary conserved proteins are associated to it: Snu13 (15.5K in human), that recognizes the internal loop [111], Nop58 and Nop1 (Fibrillarin in human) that cross-link to the U in box C and the U in box D, respectively [112]. In yeast, Nop58 and Snu13 are necessary for the accumulation of all C/D box snoRNAs [113], Nop1 is essential for the production of a subset of box C/D snoRNAs, and Nop56p is not essential for snoRNA accumulation [114].

Figure 2

Combinatorial control of transcription and translation on gene expression. Protein production depends on the resultant of transcription and translation events, in which transcriptional activators (TAs) and microRNAs (miRs), respectively, are major effectors. Other important post-transcriptional events are not indicated here, but are reviewed in [115]. Cell context specific combinations of TAs and miRs determine protein A biosynthesis:1) The cell on the left (blue context) has a large amount of transcription activators for gene A promoter and a small amount of miR interacting with the 3' UTR of gene A mRNA. As a result of the strong transcription and the low inhibition of translation, protein A is abundant in this cell. 2) On the contrary, in the cell on the right (orange context) the few TAs and the high numbers of 3' UTR interacting miRs determine a low production of protein A.

Figure 3

Regulation of neuronal differentiation through miRNAs. The neural factor NF, such as a neurotrophin (BDNF, NGF) or a neurotransmitter (glutamate, serotonin), interacts with its receptor, activating a signalling cascade that switches on transcription of selected neural genes, including specific miRNA genes as well. miRNAs, in turn, can inhibit translation of proteins regulating neuronal development, for instance a neural repressor protein. Such a regulated circuit of gene expression has been recently demonstrated for neuronal morphogenesis triggered by the cAMP-response element binding protein CREB [95]. This transcriptional activator has a central role in neural specific gene expression, being implicated in many neuronal processes like differentiation, plasticity, LPT, and memory formation. miR 132, whose transcription is activated by neurotrophins and is under direct CREB control, interacts with 3'UTR of the mRNA coding for the GTPase-activating protein p250GAP. This protein is a repressor of neuronal differentiation: its inhibition promotes neurite outgrowth.

Figure 4

Potential function of miRNAs in synaptic plasticity. Three different synapses for a single neuron are shown. Only the central one is active, as it receives an electrical pulse, and is potentiated. In the inactive synapses, translation of synaptic mRNAs (red and yellow) is prevented by miRNAs (miR) interacting with their 3'UTRs, an interaction supposedly stabilized by RNA binding proteins (RBP). A synaptic stimulus SS, represented by a neurotrophin or a neurotransmitter (e. g. BDNF and glutamate, respectively), is sensed by a receptor, in pink (e.g. TrkB or the NMDA receptor), and transmitted inside the neuron, in the vicinity of the active synapse. This signals triggers dissociation of the mRNA:miRNA:RBP complex, allowing the local translation of synaptic mRNAs. The neo-synthesized proteins (e. g. an AMPA receptor, in red, or some other synaptic component, in yellow) are utilized at the active synapse, contributing to strengthen its response.