Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Abstract

Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.F ragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, is due to the transcriptional inactivation of the Fragile X Mental Retardation 1 gene (FMR1) (1, 2). The FMR1 knockout (KO) mouse (Fmr1 −/y ) replicates phenotypes similar to human symptoms-including autistic-like behaviors, cognitive deficits, and hyperactivity-as well as abnormal dendritic spine morphology (3). FMR1 encodes Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein associated to polyribosomes and involved in the translational control of mRNAs important for synaptic plasticity (4). Consistent with a posttranscriptional function, the absence of FMRP in Fmr1 −/y mouse causes abnormal signaling of group 1 metabotropic glutamate receptors (mGluRI), leading to several forms of abnormal synaptic plasticity that rely on protein translation (5, 6). Protein expression analyses confirmed a role of FMRP in neuronal translational control (7), but the extent of this control remains unclear. Although several studies focusing on individual mRNA targets (e.g., Fmr1, Map1b, Psd95, App, etc.) suggest specific control by FMRP (2), studies of global translation, including in vivo labeling in the Fmr1 −/y mouse (8), showed thousands of neuronal proteins deregulated in the absence of FMRP, pointing toward a general translational derepression. Studies seeking to identify the transcripts controlled by FMRP identified can...

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“…It is likely that additional therapeutic targets will be designed, if feasible, against Dgkκ (6). Targeting FMRP or perhaps, even Dgkκ may not be a convenient strategy, because FMRP is also involved in the differentiation of neurons in the adult olfactory bulb and the hippocampus (16).…”

“…FMRP interacts directly with about one-third of the mRNAs that encode the synaptic proteome (5). However, this scenario of pleiotropy has been challenged recently by suggesting that the primary target of FMRP is the Diacylglycerol kinase kappa (Dgkκ), which would trigger a subsequent cascade of synaptic effects, in particular, on the glutamatergic type (6). Although the issue would require additional analysis, independent of whether the effects are direct or indirect, the FMRP transcriptome has identified mRNA targets associated with autism spectrum disorders (ASDs), mood disorders, and schizophrenia, which suggest potential common pathways for these clinically different diseases.…”

Promiscuous or discriminating: Has the favored mRNA target of Fragile X Mental Retardation Protein been overlooked?

“…For example, the most heavily cited set of FMRP targets in the mouse (3) comprises some 842 genes and was described by the authors as a "likely underestimate of the true number of targets." In striking contrast to all previous work, Tabet et al (4) contend that FMRP has one primary binding target (Fig. 1).…”

“…activation of group 1 metabotropic glutamate receptors (mGluRI), and Tabet et al (4) show that this pathway is also defective when FMRP is absent. These new observations suggest that the regulation of DgkΚ expression by FMRP is the crucial link between synaptic activity and downstream signaling pathways.…”

“…The work of Tabet et al (4) suggests a major revision of the mechanism by which this might occur. Tabet et al (4) posit that altered DAG/PA levels are the cause of the broad enhancement of protein translation frequently observed in FXS models (7). Indeed, this effect on translation has generally been viewed as a direct effect of FMRP, either by binding directly to specific mRNAs or to ribosomes.…”