Two studies, published in Cell and Neuron, give new insight into the possible functions of the protein FMRP. Mutations in the gene Fmr1, which encodes FMRP, cause fragile X syndrome, the most common cause of mental retardation. FMRP is known to bind to various mRNAs, but its normal function and how disruption of that function causes the syndrome are unclear.

Myashiro et al. used a new approach that allowed them to identify the RNAs that are associated with FMRP in vivo. The technique, called antibody-positioned RNA amplification (APRA), uses a monoclonal antibody to position a priming/amplification oligonucleotide close to mRNAs in the FMRP complex, leading to cDNA synthesis. The cDNA, complexed with the antibody, can subsequently be removed from the cell and amplified in vitro for identification by screening against microarrays.

Using this technique, and screening against two arrays, the authors identified more than 1,000 putative in vivo targets of FMRP binding. They then used more traditional methods — filter-binding assays and ultraviolet crosslinking — to confirm that around 60% of the mRNAs could interact directly with FMRP. Many of these mRNAs encoded proteins that are important for synaptic plasticity and neuronal development.

Myashiro et al. hypothesized that the interaction between these mRNAs and FMRP was important for regulating the distribution or abundance of proteins in neurons. They therefore compared control mice with those lacking Fmr1, and found that a subset of the mRNAs showed altered abundance and subcellular distribution in neural tissue in the Fmr1 null mice. The proteins encoded by these mRNAs were also distributed differently.

In the second study, Zalfa et al. compared the translational efficiency of various mRNAs in wild-type and Fmr1-null mice. They found that a subset of mRNAs were more efficiently translated in the knockout mice, and that the effect was most marked in synaptoneurosomal preparations. This indicates that FMRP might suppress the translation of specific mRNAs at synapses.

The authors also discovered that FMRP binds to a non-translated RNA, long known to reside at synapses, called BC1, and that blocking BC1 interferes with the ability of FMRP to associate with its target mRNAs. BC1 can also interact directly with the mRNAs that are regulated by FMRP. Zalfa et al. suggest that BC1 might be responsible for targeting FMRP to its target mRNAs.

Both of these studies identify important mRNAs, the subcellular localization and translation of which seem to be regulated by FMRP, particularly at synapses. This clearly points towards a potential mechanism for the various effects of fragile X syndrome, showing how a mutation in just one gene could disrupt many vital pathways in the nervous system.