{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T22:29:58Z","timestamp":1762900198570,"version":"3.37.3"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2016R1A5A2945889"],"award-info":[{"award-number":["NRF-2016R1A5A2945889"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002701","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2020R1A6C101A191"],"award-info":[{"award-number":["2020R1A6C101A191"]}],"id":[{"id":"10.13039\/501100002701","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although Kr\u00fcppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20\u00a0months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (<jats:italic>Pld3<\/jats:italic>) were observed. Among them, <jats:italic>Pld3<\/jats:italic> alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212\u2013PLD3 relationship is important for Purkinje cell survival.\n<\/jats:p>","DOI":"10.1038\/s41598-021-02218-x","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T11:02:49Z","timestamp":1637665369000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation"],"prefix":"10.1038","volume":"11","author":[{"given":"Rin","family":"Khang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Areum","family":"Jo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hojin","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunsang","family":"Kwag","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-Yeong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Okjae","family":"Koo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinsu","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hark Kyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong-Gyu","family":"Jo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inwoo","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jee-Yin","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeong-Yun","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Song","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joo-Ho","family":"Shin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"2218_CR1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1101\/gr.4842106","volume":"16","author":"S Huntley","year":"2006","unstructured":"Huntley, S. et al. A comprehensive catalog of human KRAB-associated zinc finger genes: Insights into the evolutionary history of a large family of transcriptional repressors. Genome Res. 16, 669\u2013677 (2006).","journal-title":"Genome Res."},{"key":"2218_CR2","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/S0959-440X(00)00167-6","volume":"11","author":"JH Laity","year":"2001","unstructured":"Laity, J. H., Lee, B. M. & Wright, P. E. Zinc finger proteins: New insights into structural and functional diversity. Curr. Opin. Struct. Biol. 11, 39\u201346 (2001).","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2218_CR3","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1093\/gbe\/evu030","volume":"6","author":"H Liu","year":"2014","unstructured":"Liu, H., Chang, L. H., Sun, Y., Lu, X. & Stubbs, L. Deep vertebrate roots for mammalian zinc finger transcription factor subfamilies. Genome Biol. Evol. 6, 510\u2013525 (2014).","journal-title":"Genome Biol. Evol."},{"key":"2218_CR4","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.cell.2011.02.010","volume":"144","author":"JH Shin","year":"2011","unstructured":"Shin, J. H. et al. PARIS (ZNF746) repression of PGC-1\u03b1 contributes to neurodegeneration in Parkinson\u2019s disease. Cell 144, 689\u2013702 (2011).","journal-title":"Cell"},{"key":"2218_CR5","doi-asserted-by":"publisher","first-page":"11696","DOI":"10.1073\/pnas.1500624112","volume":"112","author":"DA Stevens","year":"2015","unstructured":"Stevens, D. A. et al. Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration. Proc. Natl. Acad. Sci. U. S. A. 112, 11696\u201311701 (2015).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2218_CR6","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.ydbio.2009.04.030","volume":"331","author":"H Okado","year":"2009","unstructured":"Okado, H. et al. The transcriptional repressor RP58 is crucial for cell-division patterning and neuronal survival in the developing cortex. Dev. Biol. 331, 140\u2013151 (2009).","journal-title":"Dev. Biol."},{"key":"2218_CR7","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/cdd.2011.144","volume":"19","author":"C Xiang","year":"2012","unstructured":"Xiang, C. et al. RP58\/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion. Cell Death Differ. 19, 692\u2013702 (2012).","journal-title":"Cell Death Differ."},{"key":"2218_CR8","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.1242\/dev.075606","volume":"139","author":"V Baubet","year":"2012","unstructured":"Baubet, V. et al. Rp58 is essential for the growth and patterning of the cerebellum and for glutamatergic and GABAergic neuron development. Development 139, 1903\u20131909 (2012).","journal-title":"Development"},{"key":"2218_CR9","doi-asserted-by":"publisher","first-page":"4","DOI":"10.21767\/2573-5349.100017","volume":"3","author":"H Li","year":"2018","unstructured":"Li, H., Lu, M. & Liu, X. Zinc-finger proteins in brain development and mental illness. J. Transl. Neurosci. 3, 4 (2018).","journal-title":"J. Transl. Neurosci."},{"key":"2218_CR10","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1111\/j.1742-4658.2005.04601.x","volume":"272","author":"A Munck","year":"2005","unstructured":"Munck, A., B\u00f6hm, C., Seibel, N. M., Hosseini, H. Z. & Hampe, W. Hu-K4 is a ubiquitously expressed type 2 transmembrane protein associated with the endoplasmic reticulum. FEBS J. 272, 1718\u20131726 (2005).","journal-title":"FEBS J."},{"key":"2218_CR11","doi-asserted-by":"publisher","first-page":"31494","DOI":"10.1074\/jbc.273.47.31494","volume":"273","author":"KM Pedersen","year":"1998","unstructured":"Pedersen, K. M., Finsen, B., Celis, J. E. & Jensen, N. A. Expression of a novel murine phospholipase D homolog coincides with late neuronal development in the forebrain. J. Biol. Chem. 273, 31494\u201331504 (1998).","journal-title":"J. Biol. Chem."},{"key":"2218_CR12","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/nature12825","volume":"505","author":"C Cruchaga","year":"2014","unstructured":"Cruchaga, C. et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer\u2019s disease. Nature 505, 550\u2013554 (2014).","journal-title":"Nature"},{"key":"2218_CR13","doi-asserted-by":"publisher","first-page":"2860","DOI":"10.1093\/brain\/awx251","volume":"140","author":"EAR Nibbeling","year":"2017","unstructured":"Nibbeling, E. A. R. et al. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain 140, 2860\u20132878 (2017).","journal-title":"Brain"},{"key":"2218_CR14","doi-asserted-by":"publisher","first-page":"6064","DOI":"10.1021\/cr200296t","volume":"111","author":"PE Selvy","year":"2011","unstructured":"Selvy, P. E., Lavieri, R. R., Lindsley, C. W. & Brown, H. A. Phospholipase D: Enzymology, functionality, and chemical modulation. Chem. Rev. 111, 6064\u20136119 (2011).","journal-title":"Chem. Rev."},{"key":"2218_CR15","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1016\/j.celrep.2017.12.100","volume":"22","author":"AC Gonzalez","year":"2018","unstructured":"Gonzalez, A. C. et al. Unconventional trafficking of mammalian phospholipase D3 to lysosomes. Cell Rep. 22, 1040\u20131053 (2018).","journal-title":"Cell Rep."},{"key":"2218_CR16","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41582-018-0051-6","volume":"14","author":"T Ashizawa","year":"2018","unstructured":"Ashizawa, T., \u00d6z, G. & Paulson, H. L. Spinocerebellar ataxias: Prospects and challenges for therapy development. Nat. Rev. Neurol. 14, 590\u2013605 (2018).","journal-title":"Nat. Rev. Neurol."},{"key":"2218_CR17","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1093\/jmcb\/mjy089","volume":"11","author":"J Peng","year":"2019","unstructured":"Peng, J. et al. Single-cell transcriptomes reveal molecular specializations of neuronal cell types in the developing cerebellum. J. Mol. Cell Biol. 11, 636\u2013648 (2019).","journal-title":"J. Mol. Cell Biol."},{"key":"2218_CR18","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/nprot.2013.032","volume":"8","author":"A Bertola","year":"2013","unstructured":"Bertola, A., Mathews, S., Ki, S. H., Wang, H. & Gao, B. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat. Protoc. 8, 627\u2013637 (2013).","journal-title":"Nat. Protoc."},{"key":"2218_CR19","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/nature21683","volume":"543","author":"M Imbeault","year":"2017","unstructured":"Imbeault, M., Helleboid, P. Y. & Trono, D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature 543, 550\u2013554 (2017).","journal-title":"Nature"},{"key":"2218_CR20","doi-asserted-by":"publisher","first-page":"e78","DOI":"10.1093\/brain\/awy258","volume":"141","author":"AC Gonzalez","year":"2018","unstructured":"Gonzalez, A. C. et al. PLD3 and spinocerebellar ataxia. Brain 141, e78 (2018).","journal-title":"Brain"},{"key":"2218_CR21","doi-asserted-by":"publisher","first-page":"e79","DOI":"10.1093\/brain\/awy259","volume":"141","author":"KY Ma","year":"2018","unstructured":"Ma, K. Y. & Verbeek, D. S. Reply: PLD3 and spinocerebellar ataxia. Brain 141, e79 (2018).","journal-title":"Brain"},{"key":"2218_CR22","doi-asserted-by":"publisher","first-page":"4509","DOI":"10.1073\/pnas.91.10.4509","volume":"91","author":"JF Margolin","year":"1994","unstructured":"Margolin, J. F. et al. Kr\u00fcppel-associated boxes are potent transcriptional repression domains. Proc. Natl. Acad. Sci. U. S. A. 91, 4509\u20134513 (1994).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2218_CR23","doi-asserted-by":"publisher","first-page":"18000","DOI":"10.1074\/jbc.M001499200","volume":"275","author":"H Peng","year":"2000","unstructured":"Peng, H. et al. Biochemical analysis of the Kruppel-associated box (KRAB) transcriptional repression domain. J. Biol. Chem. 275, 18000\u201318010 (2000).","journal-title":"J. Biol. Chem."},{"key":"2218_CR24","doi-asserted-by":"publisher","first-page":"268","DOI":"10.2174\/13892029113149990002","volume":"14","author":"A Lupo","year":"2013","unstructured":"Lupo, A. et al. KRAB-zinc finger proteins: A repressor family displaying multiple biological functions. Curr. Genomics 14, 268\u2013278 (2013).","journal-title":"Curr. Genomics"},{"key":"2218_CR25","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.bbrc.2004.05.182","volume":"320","author":"Z Yi","year":"2004","unstructured":"Yi, Z. et al. A novel KRAB zinc-finger protein, ZNF480, expresses in human heart and activates transcriptional activities of AP-1 and SRE. Biochem. Biophys. Res. Commun. 320, 409\u2013415 (2004).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2218_CR26","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1074\/jbc.M109.063032","volume":"285","author":"S Frietze","year":"2010","unstructured":"Frietze, S., Lan, X., Jin, V. X. & Farnham, P. J. Genomic targets of the KRAB and SCAN domain-containing zinc finger protein 263. J. Biol. Chem. 285, 1393\u20131403 (2010).","journal-title":"J. Biol. Chem."},{"key":"2218_CR27","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1097\/00041433-200404000-00013","volume":"15","author":"G Schmitz","year":"2004","unstructured":"Schmitz, G., Heimerl, S. & Langmann, T. Zinc finger protein ZNF202 structure and function in transcriptional control of HDL metabolism. Curr. Opin. Lipidol. 15, 199\u2013208 (2004).","journal-title":"Curr. Opin. Lipidol."},{"key":"2218_CR28","doi-asserted-by":"publisher","first-page":"3544","DOI":"10.1093\/hmg\/ddq270","volume":"19","author":"F Florio","year":"2010","unstructured":"Florio, F. et al. Biochemical and functional interaction between ZNF224 and ZNF255, two members of the Kruppel-like zinc-finger protein family and WT1 protein isoforms. Hum. Mol. Genet. 19, 3544\u20133556 (2010).","journal-title":"Hum. Mol. Genet."},{"key":"2218_CR29","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.bbrc.2007.08.180","volume":"363","author":"J Li","year":"2007","unstructured":"Li, J. et al. ZNF307, a novel zinc finger gene suppresses p53 and p21 pathway. Biochem. Biophys. Res. Commun. 363, 895\u2013900 (2007).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2218_CR30","doi-asserted-by":"publisher","first-page":"9326","DOI":"10.1074\/jbc.M107702200","volume":"277","author":"AT Conroy","year":"2002","unstructured":"Conroy, A. T. et al. A novel zinc finger transcription factor with two isoforms that are differentially repressed by estrogen receptor-alpha. J. Biol. Chem. 277, 9326\u20139334 (2002).","journal-title":"J. Biol. Chem."},{"key":"2218_CR31","doi-asserted-by":"publisher","first-page":"e101220","DOI":"10.15252\/embj.2018101220","volume":"38","author":"PY Helleboid","year":"2019","unstructured":"Helleboid, P. Y. et al. The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification. EMBO J. 38, e101220 (2019).","journal-title":"EMBO J."},{"key":"2218_CR32","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s40673-016-0055-1","volume":"3","author":"PD Shanmugarajah","year":"2016","unstructured":"Shanmugarajah, P. D. et al. Alcohol-related cerebellar degeneration: Not all down to toxicity?. Cerebellum Ataxias 3, 17 (2016).","journal-title":"Cerebellum Ataxias"},{"key":"2218_CR33","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1007\/s12311-008-0034-z","volume":"7","author":"P Jaatinen","year":"2008","unstructured":"Jaatinen, P. & Rintala, J. Mechanisms of ethanol-induced degeneration in the developing, mature, and aging cerebellum. Cerebellum 7, 332\u2013347 (2008).","journal-title":"Cerebellum"},{"key":"2218_CR34","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s12311-010-0173-x","volume":"9","author":"M Manto","year":"2010","unstructured":"Manto, M. Cerebellar lingula thickness as a novel risk factor for alcohol and drug abuse. Cerebellum 9, 145\u2013147 (2010).","journal-title":"Cerebellum"},{"key":"2218_CR35","first-page":"51785","volume":"91","author":"KS Tatem","year":"2014","unstructured":"Tatem, K. S. et al. Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. J. Vis. Exp. 91, 51785 (2014).","journal-title":"J. Vis. Exp."},{"key":"2218_CR36","doi-asserted-by":"publisher","first-page":"7899","DOI":"10.1523\/JNEUROSCI.1396-07.2007","volume":"27","author":"TS Tang","year":"2007","unstructured":"Tang, T. S., Chen, X., Liu, J. & Bezprozvanny, I. Dopaminergic signaling and striatal neurodegeneration in Huntington\u2019s disease. J. Neurosci. 27, 7899\u20137910 (2007).","journal-title":"J. Neurosci."},{"key":"2218_CR37","first-page":"8","volume":"8","author":"RJ Carter","year":"2001","unstructured":"Carter, R. J., Morton, J. & Dunnett, S. B. Motor coordination and balance in rodents. Curr. Protoc. Neurosci. 8, 8\u201312 (2001).","journal-title":"Curr. Protoc. Neurosci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02218-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02218-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02218-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T17:44:36Z","timestamp":1670089476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02218-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,23]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["2218"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-02218-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2021,11,23]]},"assertion":[{"value":"7 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22745"}}