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

Abstract

Fragile X syndrome (FXS), the most common heritable cause of intellectual disability, is caused by the loss of the RNA-binding protein Fragile X Mental Retardation Protein (FMRP). FMRP is thought to bind neuronal mRNA transcripts, traffic them to synapses, and regulate their translation (1). Based on the assumption that insight into disease mechanism can be gained by understanding which targets are regulated, much effort has been put into identifying the transcripts bound by FMRP. The result of combined efforts from multiple laboratories, using multiple approaches, is a large and somewhat overlapping set of FMRP targets (2). To date, the interpretation of these disparate results is that FMRP is a promiscuous binder with a diverse set of largely synaptic function-linked target transcripts. 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). Fig. 1. The current model of how lack of FMRP gives rise to excessive translation ( Left ) has FMRP exerting a direct effect on the translation of a wide range of transcripts. Work by Tabet et al. (4) ( Right ) suggests that DgkK mRNA is the primary binding target of FMRP and that FXS phenotypes (including excessive translation) are mediated primarily through altered DgkK signaling. Like many of the previous studies, the authors performed cross-linking immunoprecipitation (CLIP) on FMRP, in their case from cultured mouse cortical neurons. To reduce false positives they compared the immunoprecipitated RNAs to those immunoprecipitated from cells lacking FMRP. Using two different antibodies, the authors find that FMRP associates predominantly with one unique mRNA, diacylglycerol kinase kappa ( DgkK ), a recently identified master regulator … [↵][1]1To whom correspondence should be addressed. Email: aoifem{at}ebi.ac.uk. [1]: #xref-corresp-1-1