TY - JOUR
T1 - Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration
AU - Joyce, Peter I.
AU - Fratta, Pietro
AU - Landman, Allison S.
AU - Mcgoldrick, Philip
AU - Wackerhage, Henning
AU - Groves, Michael
AU - Busam, Bharani Shiva
AU - Galino, Jorge
AU - Corrochano, Silvia
AU - Beskina, Olga A.
AU - Esapa, Christopher
AU - Ryder, Edward
AU - Carter, Sarah
AU - Stewart, Michelle
AU - Codner, Gemma
AU - Hilton, Helen
AU - Teboul, Lydia
AU - Tucker, Jennifer
AU - Lionikas, Arimantas
AU - Estabel, Jeanne
AU - Ramirez-Solis, Ramiro
AU - White, Jacqueline K.
AU - Brandner, Sebastian
AU - Plagnol, Vincent
AU - Bennet, David L. H.
AU - Abramov, Andrey Y.
AU - Greensmith, Linda
AU - Fisher, Elizabeth M. C.
AU - Acevedo-Arozena, Abraham
N1 - Acknowledgements
We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016.
Conflict of Interest statement. None declared.
Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.
PY - 2016/1/15
Y1 - 2016/1/15
N2 - 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.
AB - 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.
U2 - 10.1093/hmg/ddv471
DO - 10.1093/hmg/ddv471
M3 - Article
C2 - 26604141
VL - 25
SP - 291
EP - 307
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 2
ER -