Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Abstract

SUMMARYFragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

“…It is easy to envision how tissue-and development-stage-specific HS modifications could coordinate HSPG/Mmp-dependent functions, thereby differentially regulating diverse signaling events, which enable context-specific responses instructed by the extracellular environment. Future work will examine how dual inputs of the HSPG co-receptor function and how Mmp proteolytic cleavage coordinates Wnt trans-synaptic signaling during synaptogenesis, particularly in the context of our Fragile X syndrome (FXS) disease model (Coffee et al, 2010;Tessier and Broadie, 2012). Given that both loss or inhibition Mmp (Siller and Broadie, 2011) and correction of HSPG elevation (Friedman et al, 2013) independently alleviate synaptic defects in the FXS disease state, the overlapping mechanism provides an exciting avenue to therapeutic interventions for FXS and, potentially, related intellectual disability and autism spectrum disorders.…”

Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP

“…the motifs in FXR1P and FXR2P, brain-expressed autosomal paralogs of FMRP (35), which do not appear to compensate for the loss of FMRP function in FXS patients and Drosophila FXS model (36) (Fig. 1A and see SI Appendix, Fig.…”

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…Learning and memory in dFmr1 mutant flies Two main behavioral paradigms have been described to investigate learning and memory in the Drosophila model of FXS, courtship, and olfactory conditioning (McBride et al 2005;Bolduc et al 2008;Coffee et al 2010Coffee et al , 2012Kanellopoulos et al 2012;Gatto et al 2014). In 2005, using the "courtship-conditioning paradigm," McBride et al investigated learning in dFmr1 mutant flies for the first time.…”