Abstract
Zinc finger motifs are distributed amongst many eukaryotic protein families, directing nucleic acid–protein and protein–protein interactions. Zinc finger protein 106 (ZFP106) has previously been associated with roles in immune response, muscle differentiation, testes development and DNA damage, although little is known about its specific function. To further investigate the function of ZFP106, we performed an in-depth characterization of Zfp106 deficient mice (Zfp106−/−), and we report a novel role for ZFP106 in motor and sensory neuronal maintenance and survival. Zfp106−/− mice develop severe motor abnormalities, major deficits in muscle strength and histopathological changes in muscle. Intriguingly, despite being highly expressed throughout the central nervous system, Zfp106−/− mice undergo selective motor and sensory neuronal and axonal degeneration specific to the spinal cord and peripheral nervous system. Neurodegeneration does not occur during development of Zfp106−/− mice, suggesting that ZFP106 is likely required for the maintenance of mature peripheral motor and sensory neurons. Analysis of embryonic Zfp106−/− motor neurons revealed deficits in mitochondrial function, with an inhibition of Complex I within the mitochondrial electron transport chain. Our results highlight a vital role for ZFP106 in sensory and motor neuron maintenance and reveal a novel player in mitochondrial dysfunction and neurodegeneration.
Highlights
Zinc finger protein 106 (ZFP106) is a zinc finger protein with proposed roles in transcriptional control, RNA metabolism, the immune response, muscle development and differentiation and testes development [1,2,3]
Mice homozygous for the tm1a(KOMP)Wtsi allele in Zfp106 (Zfp106−/−) are born in Mendelian ratios and both Zfp106−/−male and female mice develop an abnormal gait from ∼3 weeks of age, which deteriorates with age, causing animals to inaccurately place their limbs, especially their hindlimbs, when walking across a wire grate (Supplementary Material, Movie S1)
The unbiased RNA-seq expression data show that whilst some Zfp106 expression remains in spinal cords of Zfp106−/− mice, the expression levels are
Summary
ZFP106 is a zinc finger protein with proposed roles in transcriptional control, RNA metabolism, the immune response, muscle development and differentiation and testes development [1,2,3]. ZFP106 has been identified as a novel factor regulating transcription initiation by targeting RNA-polymerase I to the promoter of ribosomal RNA genes [5], linking for the first time ZFP106 function and RNA metabolism. Zfp106 encodes a 1888-amino acid protein with two N-terminal C2H2 zinc finger motifs, two C-terminal CWCH2 zinc finger motifs and seven WD40 repeats [2,3,6]. Zinc finger motifs are important for protein–protein interactions and nucleic-acid binding [7], whilst WD40 repeats are involved in protein–protein interaction and facilitate the formation of large multi-protein complexes [8]. Putative orthologues of Zfp106 are only found in mammals and exhibit a high degree of conservation between species
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