{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:10:34Z","timestamp":1787026234179,"version":"build-2736575974"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007343","name":"Universit\u00e0 degli Studi di Brescia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007343","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Mitochondrial membrane Protein Associated Neurodegeneration (MPAN) is a rare genetic disorder due to mutations in\n                    <jats:italic>C19orf12<\/jats:italic>\n                    gene. In most cases, the disorder is transmitted as an autosomal recessive trait and the main clinical features are progressive spastic para\/tetraparesis, dystonia, motor axonal neuropathy, parkinsonisms, psychiatric symptoms, and optic atrophy. Besides iron accumulation in the globus pallidus and substantia nigra, the neuropathology shows features also observed in Parkinson\u2019s Disease brains, such as \u03b1-synuclein-positive Lewy bodies and hyperphosphorylated tau. Mutations in the gene have been found in other neurodegenerative disorders, including PD, hereditary spastic paraplegia, pallido-pyramidal syndrome, and amyotrophic lateral sclerosis. The biological function of\n                    <jats:italic>C19orf12<\/jats:italic>\n                    gene is poorly defined. In humans, it codes for two protein isoforms: the longer one is present in mitochondria, endoplasmic reticulum, and contact regions between mitochondria and ER. Mutations in the gene appear to be linked to defects in mitochondrial activity, lipid metabolism and autophagy\/mitophagy. To increase the available tools for the investigation of MPAN pathogenesis, we generated a new animal model in zebrafish embryos. The zebrafish genome contains four co-orthologs of human\n                    <jats:italic>C19orf12<\/jats:italic>\n                    . One of them, located on chromosome 18, is expressed at higher levels at early stages of development. We downregulated its expression by microinjecting embryos with a specific ATG-blocking morpholino, and we analyzed embryonal development. Most embryos showed morphological defects such as unsettled brain morphology, with smaller head and eyes, reduced yolk extension, tilted and thinner tail. The severity of the defects progressively increased and all injected embryos died within 7 days post fertilization. Appropriate controls confirmed the specificity of the observed phenotype. Changes in the expression and distribution of neural markers documented a defective neuronal development, particularly evident in the eyes, the optic tectum, the midbrain-hindbrain boundary; Rohon Beard and dorsal root ganglia neurons were also affected. Phalloidin staining evidenced a significant perturbation of musculature formation that was associated with defective locomotor behavior. These data are consistent with the clinical features of MPAN and support the validity of the model to investigate the pathogenesis of the disease and evaluate molecules with potential therapeutic effect.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2020.596069","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T01:20:35Z","timestamp":1608686435000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["The Downregulation of c19orf12 Negatively Affects Neuronal and Musculature Development in Zebrafish Embryos"],"prefix":"10.3389","volume":"8","author":[{"given":"Luca","family":"Mignani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Zizioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Borsani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Finazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18030596","article-title":"Zebrafish embryo as an in vivo model for behavioral and pharmacological characterization of methylxanthine drugs.","volume":"18","author":"Basnet","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1242\/dev.124.22.4557","article-title":"The activity of neurogenin1 is controlled by local cues in the zebrafish embryo.","volume":"124","author":"Blader","year":"1997","journal-title":"Development"},{"key":"B3","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/s0925-4773(02)00413-6","article-title":"Multiple regulatory elements with spatially and temporally distinct activities control neurogenin1 expression in primary neurons of the zebrafish embryo.","volume":"120","author":"Blader","year":"2003","journal-title":"Mech. Dev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.jphysparis.2003.10.009","article-title":"Steps during the development of the zebrafish locomotor network.","volume":"97","author":"Brustein","year":"2003","journal-title":"J. Physiol. Paris"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2010.00011","article-title":"The specification of glycinergic neurons and the role of glycinergic transmission in development.","volume":"3","author":"Chalphin","year":"2010","journal-title":"Front. Mol. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1007\/s00415-012-6521-7","article-title":"C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.","volume":"259","author":"Deschauer","year":"2012","journal-title":"J. Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1002\/jimd.12026","article-title":"Inborn errors of coenzyme A metabolism and neurodegeneration.","volume":"42","author":"Di Meo","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1080\/13554794.2018.1506038","article-title":"Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review.","volume":"24","author":"Du\u0161ek","year":"2018","journal-title":"Neurocase"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2017.00064","article-title":"Midbrain-hindbrain boundary morphogenesis: at the intersection of Wnt and Fgf Signaling.","volume":"11","author":"Gibbs","year":"2017","journal-title":"Front. Neuroanat."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.736","article-title":"Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).","volume":"7","author":"Gregory","year":"2019","journal-title":"Mol. Genet. Genom. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/j.ajhg.2011.09.007","article-title":"Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.","volume":"89","author":"Hartig","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1056\/NEJMoa020817","article-title":"Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome.","volume":"348","author":"Hayflick","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1212\/WNL.0b013e31827e07be","article-title":"New NBIA subtype. genetic, clinical, pathologic, and radiographic features of MPAN.","volume":"80","author":"Hogarth","year":"2013","journal-title":"Neurology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1002\/mds.24980","article-title":"A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy.","volume":"27","author":"Horvath","year":"2012","journal-title":"Mov. Disord."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089439","article-title":"Impairment of Drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration.","volume":"9","author":"Iuso","year":"2014","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/srep37660","article-title":"Down-regulation of coasy, the gene associated with NBIA-VI, reduces Bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish.","volume":"6","author":"Khatri","year":"2016","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1007\/s12017-018-8508-8","article-title":"Overexpression of human mutant PANK2 proteins affects development and motor behavior of zebrafish embryos.","volume":"21","author":"Khatri","year":"2018","journal-title":"Neuromol. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"9644","DOI":"10.1523\/JNEUROSCI.1225-14.2014","article-title":"A hybrid electrical\/chemical circuit in the spinal cord generates a transient embryonic motor behavior.","volume":"34","author":"Knogler","year":"2014","journal-title":"J. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1002\/(sici)1097-0177(199809)213:1<92::aid-aja9>3.0.co;2-t","article-title":"Expression of zebrafish bHLH genes ngn1 and nrd defines distinct stages of neural differentiation.","volume":"213","author":"Korzh","year":"1998","journal-title":"Dev. Dyn."},{"key":"B20","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.gene.2013.11.039","article-title":"C19orf12 mutation leads to a pallido-pyramidal syndrome.","volume":"537","author":"Kruer","year":"2014","journal-title":"Gene"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1002\/humu.22378","article-title":"Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.","volume":"34","author":"Landour\u00e9","year":"2013","journal-title":"Hum. Mutat."},{"key":"B22","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/s0959-4388(97)80115-8","article-title":"Basic helix-loop-helix genes in neural development.","volume":"7","author":"Lee","year":"1997","journal-title":"Curr. Opin. Neurobiol."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00099","article-title":"Neurodegeneration with brain iron accumulation. update on pathogenic mechanisms.","volume":"5","author":"Levi","year":"2014","journal-title":"Front. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ph12010027","article-title":"Neurodegeneration with brain iron accumulation disorders. valuable models aimed at understanding the pathogenesis of iron deposition.","volume":"12","author":"Levi","year":"2019","journal-title":"Pharmaceuticals"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1093\/brain\/awt043","article-title":"A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation.","volume":"136","author":"Mahmood","year":"2013","journal-title":"Brain"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-015-0555-z","article-title":"New zebrafish models of neurodegeneration.","volume":"15","author":"Mart\u00edn-Jim\u00e9nez","year":"2015","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1089\/zeb.2008.0564","article-title":"Modular laboratory exercises to analyze the development of zebrafish motor behavior.","volume":"6","author":"McKeown","year":"2009","journal-title":"Zebrafish"},{"key":"B28","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/s0361-9230(01)00694-3","article-title":"Expression domains of neuroD (n.d.) in the early postembryonic zebrafish brain.","volume":"57","author":"Mueller","year":"2002","journal-title":"Brain Res. Bull."},{"key":"B29","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/s0165-3806(02)00583-7","article-title":"Anatomy of neurogenesis in the early zebrafish brain.","volume":"140","author":"Mueller","year":"2003","journal-title":"Brain Res. Dev. Brain Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.spen.2012.03.006","article-title":"C19orf12 and FA2H mutations are rare in Italian patients with neurodegeneration with brain iron accumulation.","volume":"19","author":"Panteghini","year":"2012","journal-title":"Semin. Pediatr. Neurol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1002\/dvdy.20375","article-title":"Dazed gene is necessary for late cell type development and retinal cell maintenance in the zebrafish retina.","volume":"233","author":"Perkins","year":"2005","journal-title":"Dev. Dyn."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0030078","article-title":"p53 activation by knockdown technologies.","volume":"3","author":"Robu","year":"2007","journal-title":"PLoS Genet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3927","DOI":"10.1242\/dev.099531","article-title":"Transgenic tools to characterize neuronal properties of discrete populations of zebrafish neurons.","volume":"140","author":"Satou","year":"2013","journal-title":"Development"},{"key":"B34","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.cell.2014.03.049","article-title":"CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.","volume":"157","author":"Schaffer","year":"2014","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1146\/annurev.genet.37.110801.143752","article-title":"Molecular genetics of axis formation in zebrafish.","volume":"39","author":"Schier","year":"2005","journal-title":"Annu. Rev. Genet."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2011.75","article-title":"Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega.","volume":"7","author":"Sievers","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3791\/50925","article-title":"Analysis of skeletal muscle defects in larval zebrafish by birefringence and touch-evoke escape response assays.","volume":"82","author":"Smith","year":"2013","journal-title":"J. Vis. Exp."},{"key":"B38","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/s0091-679x(04)77027-2","article-title":"Spatial and temporal expression of the zebrafish genome by large-scale in situ hybridization screening.","volume":"77","author":"Thisse","year":"2004","journal-title":"Methods Cell Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/nprot.2007.514","article-title":"High-resolution in situ hybridization to whole-mount zebrafish embryos.","volume":"3","author":"Thisse","year":"2008","journal-title":"Nat. Protoc."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029128","article-title":"Using the Tg(nrd:egfp)\/albino zebrafish line to characterize in vivo expression of neurod.","volume":"7","author":"Thomas","year":"2012","journal-title":"PLoS One"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20061296","article-title":"Zebrafish models of neurodevelopmental disorders: limitations and benefits of current tools and techniques.","volume":"20","author":"Vaz","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00185","article-title":"Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca2 +.","volume":"6","author":"Venco","year":"2015","journal-title":"Front. Genet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1089\/zeb.2018.1683","article-title":"ZF-Mapper: simple and complete freeware for fluorescence quantification in zebrafish images.","volume":"16","author":"Yamamoto","year":"2019","journal-title":"Zebrafish"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064058","article-title":"Deep mRNA sequencing analysis to capture the transcriptome landscape of zebrafish embryos and larvae.","volume":"8","author":"Yang","year":"2013","journal-title":"PLoS One"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2019.109754","article-title":"Analysis of tail coiling activity of zebrafish (Danio rerio) embryos allows for the differentiation of neurotoxicants with different modes of action.","volume":"186","author":"Zindler","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B46","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.nbd.2015.10.010","article-title":"Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease.","volume":"85","author":"Zizioli","year":"2015","journal-title":"Neurobiol. Dis."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.596069\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T17:46:02Z","timestamp":1670521562000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.596069\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,23]]},"references-count":46,"alternative-id":["10.3389\/fcell.2020.596069"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2020.596069","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,23]]},"article-number":"596069"}}