Wnd/DLK Is a Critical Target of FMRP Responsible for Neurodevelopmental and Behavior Defects in the Drosophila Model of Fragile X Syndrome

Abstract

Summary: Fragile X syndrome (FXS) is the leading heritable cause of intellectual disability and commonly co-occurs with autism spectrum disorder. Silencing of the Fmr1 gene leads to the absence of the protein product, fragile X mental retardation protein (FMRP), which represses translation of many target mRNAs. Excess translation of these targets is one cause of neuronal dysfunction in FXS. Utilizing the Drosophila model of FXS, we identified the mitogen-activated protein kinase kinase kinase (MAP3K) Wallenda/dual leucine zipper kinase (DLK) as a critical target of FMRP. dFMRP binds Wallenda mRNA and is required to limit Wallenda protein levels. In dFmr1 mutants, Wallenda signaling drives defects in synaptic development, neuronal morphology, and behavior. Pharmacological inhibition of Wallenda in larvae suppresses dFmr1 neurodevelopmental phenotypes, while adult administration prevents dFmr1 behavioral defects. We propose that in dFmr1 mutants chronic Wallenda/DLK signaling disrupts nervous system development and function and that inhibition of this kinase cascade might be a candidate therapeutic intervention for the treatment of FXS. : Russo and DiAntonio identify a dysregulated MAPK signaling pathway in the fly model of fragile X syndrome. MAP3K Wnd/DLK drives dFmr1 mutant phenotypes, and pharmacological inhibition of Wnd/DLK prevents neural dysfunction in this model, thus highlighting a possible role for Wnd/DLK in the pathophysiology of fragile X syndrome. Keywords: highwire, neurodevelopment, neurodegeneration, JNK, grooming behavior, GNE-3511, neuromuscular junction, synaptic transmission