Targeting of messenger RNAs (mRNAs) in neuron processes relies on cis-acting regulatory elements, the nature of which is poorly understood. Here, we report that approximately 30% of the bestknown dendritic mRNAs contain a guanine (G)-quadruplex consensus in their 3 0 -untranslated region. Among these mRNAs, we show by using RNA structure probing that a G-quadruplex is present in the mRNAs of two key postsynaptic proteins: PSD-95 and CaMKIIa. The G-quadruplex structure is necessary and sufficient for the potent and fast localization of mRNAs in cortical neurites and this occurs in a metabotropic glutamate receptorresponsive manner. Thus, G-quadruplex seems to be a common neurite localization signal.

Intracellular mRNA transport and local translation play a key role in neuronal physiology. Translationally repressed mRNAs are transported as a part of ribonucleoprotein (RNP) particles to distant dendritic sites, but the properties of different RNP particles and mechanisms of their repression and transport remain largely unknown. Here, we describe a new class of RNP-particles, the dendritic P-bodylike structures (dlPbodies), which are present in the soma and dendrites of mammalian neurons and have both similarities and differences to P-bodies of non-neuronal cells. These structures stain positively for a number of P-body and microRNP components, a microRNA-repressed mRNA and some translational repressors. They appear more heterogeneous than P-bodies of HeLa cells, and they rarely contain the exonuclease Xrn1 but are positive for rRNA. These particles show motorized movements along dendrites and relocalize to distant sites in response to synaptic activation. Furthermore, Dcp1a is stably associated with dlP-bodies in unstimulated cells, but exchanges rapidly on neuronal activation, concomitantly with the loss of Ago2 from dlP-bodies. Thus, dlP-bodies may regulate local translation by storing repressed mRNPs in unstimulated cells, and releasing them on synaptic activation.

Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is due to the functional deficiency of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in translational regulation of many messenger RNAs, playing key roles in synaptic morphology and plasticity. To date, no effective treatment for FXS is available. We searched for FMRP targets by HITS-CLIP during early development of multiple mouse brain regions (hippocampus, cortex and cerebellum) at a time of brain development when FMRP is most highly expressed and synaptogenesis reaches a peak. We identified the largest dataset of mRNA targets of FMRP available in brain and we defined their cellular origin. We confirmed the G-quadruplex containing structure as an enriched motif in FMRP RNA targets. In addition to four less represented motifs, our study points out that, in the brain, CTGKA is the prominent motif bound by FMRP, which recognizes it when not engaged in Watson–Crick pairing. All of these motifs negatively modulated the expression level of a reporter protein. While the repertoire of FMRP RNA targets in cerebellum is quite divergent, the ones of cortex and hippocampus are vastly overlapping. In these two brain regions, the Phosphodiesterase 2a (Pde2a) mRNA is a prominent target of FMRP, which modulates its translation and intracellular transport. This enzyme regulates the homeostasis of cAMP and cGMP and represents a novel and attractive therapeutic target to treat FXS.

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