Synaptic control of local translation: the plot thickens with new characters

Abstract

The production of proteins from mRNAs localized at the synapse ultimately controls the strength of synaptic transmission, thereby affecting behavior and cognitive functions. The regulated transcription, processing, and transport of mRNAs provide dynamic control of the dendritic transcriptome, which includes thousands of messengers encoding multiple cellular functions. Translation is locally modulated by synaptic activity through a complex network of RNA-binding proteins (RBPs) and various types of non-coding RNAs (ncRNAs) including BC-RNAs, microRNAs, piwi-interacting RNAs, and small interference RNAs. The RBPs FMRP and CPEB play a well-established role in synaptic translation, and additional regulatory factors are emerging. The mRNA repressors Smaug, Nanos, and Pumilio define a novel pathway for local translational control that affects dendritic branching and spines in both flies and mammals. Recent findings support a role for processing bodies and related synaptic mRNA-silencing foci (SyAS-foci) in the modulation of synaptic plasticity and memory formation. The SyAS-foci respond to different stimuli with changes in their integrity thus enabling regulated mRNA release followed by translation. CPEB, Pumilio, TDP-43, and FUS/TLS form multimers through low-complexity regions related to prion domains or polyQ expansions. The oligomerization of these repressor RBPs is mechanistically linked to the aggregation of abnormal proteins commonly associated with neurodegeneration. Here, we summarize the current knowledge on how specificity in mRNA translation is achieved through the concerted action of multiple pathways that involve regulatory ncRNAs and RBPs, the modification of translation factors, and mRNA-silencing foci dynamics.

Fig. 1

The dendritic transcriptome and its regulation. The transport of mRNAs to dendrites depends on cis-acting elements and may involve alternative UTRs that contribute to localization and translational regulation. Synaptic activity affects both nuclear and cytoplasmic mRNA processing, which involves specific factors that are depicted in association with the mRNAs in several colors. Two independent mechanisms for the nuclear export of mRNAs directed to the synapse are known: the exit of mRNPs through the nuclear pore and the exit of nuclear RNA granules (red spheres) through budding and fusion of the nuclear membrane. Once in the cytoplasm, the RNA granules (green and red spheres) are transported to the post-synaptic regions by the action of microtubule-dependent molecular motors. Translational regulation at the post-synapse involves multiple mechanisms and molecules: the control of RNA granule integrity; the activation and inactivation of translation factors by mTOR and other pathways; the calpain-mediated decay of the PABP inhibitor PAIP2; non-coding RNAs that are locally modulated at several levels, including biogenesis and stability; and a great variety of RBPs whose aggregation and activity are regulated by synaptic stimulation

Fig. 2

Mechanisms for translational regulation at the synapse. Several RBPs and non-coding RNAs coordinate the translation of localized mRNAs. The miRNA pathway (upper left) regulates numerous transcripts and is locally controlled at several levels by synaptic activity. MicroRNA biogenesis is stimulated through the activation of DICER by HIV-TAR binding protein (TRBP), and pre-miRNA decay is stimulated by the Lin28/Dis3l2 pathway. MicroRNA-mediated silencing is modulated by FMRP and Pumilio (double arrows) and by PrPc in association with multivesicular bodies (MVB). The miRNA pathway is antagonized by competitive endogenous RNAs that act as miRNA sponges to neutralize specific miRNAs. FMRP (upper right) is an important disease-associated repressor that affects the translation of hundreds of transcripts carrying specific motifs via multiple pathways. Dysregulation of the FMRP pathway is causative of Fragil X mental retardation syndrome (FSMRS) and autism spectrum disorders (ASD). CPEB (bottom right) binds the specific motif termed CPE and recruits the deadenylase PARN and the poly(A) polymerase GLD2. CPEB bidirectionally regulates the deadenylation or cytoplasmic polyadenylation of several transcripts. Smaug, Nanos, and Pumilio (bottom left) define a novel regulatory network conserved in mammals and invertebrates. Mammalian Smaug1/Samd4a controls synaptic CaMKII alpha mRNA and potentially several other transcripts carrying SREs, including Nanos 1 mRNA. Drosophila Smaug regulates Nanos, which together with Pumilio and Brat affects the translation of a number of Drosophila neuronal transcripts. The effect of Pumilio on paralytic/Scn1a, Dlg, and 4E mRNAs has been demonstrated in both Drosophila and mammalian models, and the repression of AChE mRNA by Pumilio 2 has been shown in the mammalian neuromuscular junction. Mammalian miR-134 regulates Pumilio 2 upon synaptic activity. A potential functional interaction between Pumilio and CPEB is indicated by double arrows

Fig. 3

PBs and Smaug1 foci in dendrites and dendritic spines. a Smaug1/Samd4a knockdown in hippocampal neurons provokes the presence of numerous thin dendritic spines. Deconvoluted confocal Z-stack images of ECFP-expressing neurons are shown. Bar 1 μm. b Smaug1/Samd4a forms mRNA-silencing foci in mature hippocampal neurons. c Smaug1 foci are present in approximately 60 % of the dendritic spines, visualized by transient ECFP expression. d–f The PB markers DCP1a, Hedls, and Rck/p54 form dendritic foci. Whereas Hedls and Rck/p54 are mostly restricted to the dendritic shaft, 40 % of the synapses contain DCP1a [14, 35, 39]. Bars in b–f 10 μm; magnifications 1 μm

Fig. 4

mRNA-silencing foci at the synapse. Translational regulation at the synapse involves multiple mRNA-silencing foci, which are regulated by synaptic activity and thus termed synaptic activity-regulated mRNA-silencing foci (SyAS-foci). Among others, Smaug1 foci (S-foci), a plethora of PBs with various composition and granules containing FMRP or Caprin1/RNG105 are present at the post-synapse. These different SyAS-foci respond to specific stimuli, displaying changes in motility or integrity. Their dissolution allows for the release of mRNA followed by translation. S-foci respond to NMDAR stimulation and remain unaltered upon AMPAR stimulation. AMPAR or mGluR stimulation provokes the dissolution of FMRP granules in the synaptic surroundings, whereas NMDAR activation has no effect. Caprin1/RNG105 granules dissolve upon BDNF Receptor (BDNFR) stimulation [5, 14, 155]. The exchange of mRNPs between PBs and the cytosol increases upon NMDAR activation, which may induce PB disassembly. PBs also respond to BDNF; short exposure increases the number of PBs in dendrites, whereas long exposure triggers their dissolution [22, 37, 39] (not shown). In most cases, the identity of the released transcripts is only partially known. Speculatively, a given mRNA species may associate with multiple SyAS-foci, thus facilitating its regulation upon different stimuli. NMDAR stimulation globally represses translation by the inactivation of eEF2, whereas mGluR and BDNFR stimulation enhances protein synthesis through the mTOR and other pathways

Fig. 5

The mTOR pathway is a major regulator of multiple cellular networks and responds to synaptic stimulation. The activation of the translation regulatory complex mTORC1 is directed by the upstream kinases PI3K and AKT. mTOR activation in non-neuronal cells depends on its localization to the lysosome membrane and a complex mechanism that involves several regulatory proteins (not shown) [176]. The role of lysosomes or functionally related membrane organelles in the regulation of mTOR upon synaptic stimulation is unknown. The inactivation of 4EBP by mTOR facilitates the translation of TOP and TOP-like mRNAs, and eEF1A and several other molecules functionally linked to translation are regulated by this pathway. The phosphorylation of eIF4B by mTOR-activated S6K enhances the helicase activity of the eIF4A subunit, thereby facilitating translation initiation. S6K inactivates eEF2K, thus limiting the phosphorylation and inactivation of eEF2 and stimulating elongation. The translation of transcripts carrying EJCs is stimulated by S6K through SKAR. This pathway may affect the pioneer translation round and transcripts with EJCs at the 3′UTR, which are abundant in neurons [50]. Upon NMDAR activation, mTOR stabilizes the HuD targets CaMKII alpha, Homer, and GAP43 mRNAs [29] by unknown mechanisms; as a result, HuD availability is reduced and this facilitates Kv.v1 mRNA repression by miR-129. The mTOR pathway inhibits autophagy, which in turn affects miRNA-mediated silencing and further connects mTOR with mRNA regulation