title: Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106.
abstract: Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve-muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasting, and degeneration. Here we show that the nuclear zinc finger protein ZFP106 is highly enriched in skeletal muscle and is required for postnatal maintenance of myofiber innervation by motor neurons. Genetic disruption of Zfp106 in mice results in progressive ataxia and hindlimb paralysis associated with motor neuron degeneration, severe muscle wasting, and premature death by 6 mo of age. We show that ZFP106 is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes. Upon inhibition of pre-mRNA synthesis, ZFP106 translocates with other splicing factors to the nucleolus. Muscle and spinal cord of Zfp106 knockout mice displayed a gene expression signature of neuromuscular degeneration. Strikingly, altered splicing of the Nogo (Rtn4) gene locus in skeletal muscle of Zfp106 knockout mice resulted in ectopic expression of NOGO-A, the neurite outgrowth factor that inhibits nerve regeneration and destabilizes neuromuscular junctions. These findings reveal a central role for Zfp106 in the maintenance of nerve-muscle signaling, and highlight the involvement of aberrant RNA processing in neuromuscular disease pathogenesis.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Anderson
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
authors.forename: Jessica
authors.initials: J
authors.lastname: Cannavino
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Anderson
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Nelson
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: John
authors.initials: J
authors.lastname: McAnally
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bezprozvannaya
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Weichun
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; eric.olson@utsouthwestern.edu.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019282:Wasting Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016601:RNA-Binding Proteins; C116200:Zfp106 protein, mouse
keywords: ZNF106; amyotrophic lateral sclerosis (ALS); motor neuron disease (MND); neuromuscular junction (NMJ); pre-mRNA splicing