FMR1

Function

Synaptic plasticity

FMRP has a diverse array of functions throughout different areas of the neuron; however these functions have not been fully characterized. FMRP has been suggested to play roles in nucleocytoplasmic shuttling of mRNA, dendritic mRNA localization, and synaptic protein synthesis. Studies of Fragile X syndrome have significantly aided in the understanding of the functionality of FMRP through the observed effects of FMRP loss on neurons. A mouse model of Fragile X Messenger Ribonucleoprotein implicated the involvement of FMRP in synaptic plasticity. Synaptic plasticity requires the production of new proteins in response to activation of synaptic receptors. It is the production of proteins in response to stimulation which is hypothesized to allow for the permanent physical changes and altered synaptic connections that are linked with the processes of learning and memory.

Group 1 metabotropic glutamate receptor (mGluR) signaling has been implicated in playing an important role in FMRP-dependent synaptic plasticity. Post-synaptic mGluR stimulation results in the up-regulation of protein synthesis through a second messenger system. A role for mGluR in synaptic plasticity is further evidenced by the observation of dendritic spine elongation following mGluR stimulation. Furthermore, mGluR activation results in the synthesis of FMRP near synapses. The produced FMRP associates with polyribosomal complexes after mGluR stimulation, proposing the involvement of Fragile X Messenger Ribonucleoprotein in the process of translation. This further advocates a role for FMRP in synaptic protein synthesis and the growth of synaptic connections. The loss of FMRP results in an abnormal dendritic spine phenotype. Specifically, deletion of the FMR1 gene in a sample of mice resulted in an increase in spine synapse number.

Role in translation

The proposed mechanism of FMRP's effect upon synaptic plasticity are through its role as a negative regulator of translation. FMRP is an RNA-binding protein which associates with polyribosomes. The RNA-binding abilities of FMRP are dependent upon its KH domains and RGG boxes. The KH domain is a conserved motif which characterizes many RNA-binding proteins. Mutagenesis of this domain resulted in impaired FMRP binding to RNA.

FMRP has been shown to inhibit translation of mRNA. Mutation of the FMRP protein resulted in the inability to repress translation as opposed to the wild-type counterpart which was able to do so in model systems (reticulocyte lysates and Xenopus laevis oocytes). These observations were extended to the mouse brain, where crosslinking immunoprecipitation (CLIP) studies showed that FMRP binds to mRNA targets to stall ribosomes and inhibit translation, and does so in a reversible manner. In purified synaptoneurosomes, mGluR stimulation results in increased levels of FMRP target mRNAs. A study found basal levels of proteins encoded by these target mRNAs to be significantly elevated and improperly regulated in FMRP deficient mice.

FMRP translation repression can act by inhibiting the initiation of translation. FMRP directly binds CYFIP1, which in turn binds the translation initiation factor eIF4E. The FMRP-CYFIP1 complex prohibits eIF4E-dependent initiation, thereby acting to repress translation. When applied to the observed phenotype in fragile X Syndrome, the excess protein levels and reduction of translational control can be explained by the loss of translational repression by FMRP in fragile X syndrome. FMRP acts to control translation of a large group of target mRNAs; however the extent of FMRPs translational control is unknown. The protein has been shown to repress the translation of target mRNAs at synapses, including those encoding the cytoskeletal proteins Arc/Arg3.1 and MAP1B, and the CaM kinase II. In addition, FMRP binds PSD-95 and GluR1/2 mRNAs. Importantly, these FMRP-binding mRNAs play significant roles in neuronal plasticity.

FMRP translational control has been shown to be regulated by mGluR signaling. mGluR stimulation may result in the transportation of mRNA complexes to synapses for local protein synthesis. FMRP granules have been shown to localize with MAP1B mRNA and ribosomal RNA in dendrites, suggesting this complex as a whole may need to be transported to dendrites for local protein synthesis. In addition, microtubules were found to be a necessary component for the mGluR-dependent translocation of FMRP into dendrites. FMRP may play an additional role in local protein synthesis by aiding in the association of mRNA cargo and microtubules. Thus, FMRP is able to regulate transport efficacy, as well as repression of translation during transport. Finally, FMRP synthesis, ubiquitination, and proteolysis occur rapidly in response to mGluR signaling, suggesting an extremely dynamic role of the translational regulator.