{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:30:51Z","timestamp":1780108251153,"version":"3.54.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T00:00:00Z","timestamp":1574121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008052","name":"Fundaci\u00f3n Alfonso Mart\u00edn Escudero","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"DOI":"10.3389\/fnins.2019.01233","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T00:24:27Z","timestamp":1574123067000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Lowering EphA4 Does Not Ameliorate Disease in a Mouse Model for Severe Spinal Muscular Atrophy"],"prefix":"10.3389","volume":"13","author":[{"given":"Lindsay","family":"Poppe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Smolders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ru\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke","family":"Timmers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Lenaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annet","family":"Storm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lies","family":"Schoonaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antina","family":"de Boer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Van Damme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludo","family":"Van Den Bosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Robberecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Lemmens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2019,11,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1093\/hmg\/ddr067","article-title":"Increased IGF-1 in muscle modulates the phenotype of severe SMA mice.","volume":"20","author":"Bosch-Marc\u00e9","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-10-24","article-title":"Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy.","volume":"10","author":"Bowerman","year":"2012","journal-title":"BMC Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1002\/mus.880161111","article-title":"Motor unit number estimation, isometric strength, and electromyographic measures in amyotrophic lateral sclerosis.","volume":"16","author":"Bromberg","year":"1993","journal-title":"Muscle Nerve"},{"key":"B4","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJMra1603471","article-title":"Amyotrophic lateral sclerosis.","volume":"377","author":"Brown","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1093\/hmg\/11.12.1439","article-title":"Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model.","volume":"11","author":"Cifuentes-Diaz","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1101\/gr.7.4.339","article-title":"Cloning, characterization, and copy number of the murine survival motor neuron gene homolog of the spinal muscular atrophy-determining gene.","volume":"7","author":"DiDonato","year":"1997","journal-title":"Genome Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"13248","DOI":"10.1073\/pnas.95.22.13248","article-title":"EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract.","volume":"95","author":"Dottori","year":"1998","journal-title":"Neurobiology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.expneurol.2008.02.025","article-title":"Identification of a battery of tests for drug candidate evaluation in the SMN\u03947 neonate model of spinal muscular atrophy.","volume":"212","author":"El-Khodor","year":"2008","journal-title":"Exp. Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1086\/338627","article-title":"Quantitative Analyses of SMN1 and SMN2 based on real-time lightcycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.","volume":"70","author":"Feldk\u00f6tter","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus sham control in infantile-onset spinal muscular atrophy.","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.expneurol.2003.10.004","article-title":"Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.","volume":"185","author":"Fischer","year":"2004","journal-title":"Exp. Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2534","DOI":"10.1523\/jneurosci.20-07-02534.2000","article-title":"Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases.","volume":"20","author":"Frey","year":"2000","journal-title":"J. Neurosci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"9959","DOI":"10.1073\/pnas.1405803111","article-title":"Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer\u2019s disease.","volume":"111","author":"Fu","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B14","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nn1811","article-title":"Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism.","volume":"10","author":"Fu","year":"2007","journal-title":"Nat. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024636","article-title":"EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice.","volume":"6","author":"Goldshmit","year":"2011","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1126\/science.8209258","article-title":"Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation.","volume":"264","author":"Gurney","year":"1994","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1136\/JNNP.41.9.773","article-title":"A quantitative electrophysiological study of motor neurone disease.","volume":"41","author":"Hansen","year":"1978","journal-title":"J. Neurol. Neurosurg. Psychiatr."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1093\/hmg\/ddp030","article-title":"Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo.","volume":"18","author":"Heier","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1101\/gad.1941310","article-title":"Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model.","volume":"24","author":"Hua","year":"2010","journal-title":"Genes Dev."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.89970","article-title":"Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy.","volume":"2","author":"Kaifer","year":"2017","journal-title":"JCI Insight"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2552","DOI":"10.1093\/hmg\/ddn156","article-title":"Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy.","volume":"17","author":"Kariya","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1523\/JNEUROSCI.4434-08.2009","article-title":"Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice.","volume":"29","author":"Kong","year":"2009","journal-title":"J. Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1126\/science.1079641","article-title":"Role of EphA4 and EphrinB3 in local neuronal circuits that control walking.","volume":"299","author":"Kullander","year":"2003","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1093\/hmg\/ddi078","article-title":"SMN\u03947, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN.","volume":"14","author":"Le","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"B25","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/J.YDBIO.2011.05.667","article-title":"Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons.","volume":"356","author":"Lee","year":"2011","journal-title":"Dev. Biol."},{"key":"B26","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene.","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2214","DOI":"10.1093\/hmg\/ddt073","article-title":"Modifying expression of ephA4 and its downstream targets improves functional recovery after stroke.","volume":"22","author":"Lemmens","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1093\/hmg\/ddr453","article-title":"Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy.","volume":"21","author":"Ling","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","article-title":"A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.","volume":"96","author":"Lorson","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2122","DOI":"10.1016\/B978-0-444-64076-5.00038-7","article-title":"Spinal muscular atrophy.","volume":"371","author":"Lunn","year":"2008","journal-title":"Lancet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1002\/path.4080","article-title":"Synaptic defects in type i spinal muscular atrophy in human development.","volume":"229","author":"Mart\u00ednez-Hern\u00e1ndez","year":"2013","journal-title":"J. Pathol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1093\/ptj\/73.12.868","article-title":"Motor unit populations in healthy and diseased muscles.","volume":"73","author":"McComas","year":"1993","journal-title":"Phys. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-dose gene-replacement therapy for spinal muscular atrophy.","volume":"377","author":"Mendell","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1093\/hmg\/8.7.1177","article-title":"A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2.","volume":"8","author":"Monani","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1083\/jcb.200208079","article-title":"A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy.","volume":"160","author":"Monani","year":"2003","journal-title":"J. Cell Biol."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055948","article-title":"EphA4 receptor tyrosine kinase is a modulator of onset and disease severity of experimental autoimmune encephalomyelitis (EAE).","volume":"8","author":"Munro","year":"2013","journal-title":"PLoS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/nn994","article-title":"Control of hippocampal dendritic spine morphology through ephrin-A3\/EphA4 signaling.","volume":"6","author":"Murai","year":"","journal-title":"Nat. Neurosci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/j.mcn.2003.08.006","article-title":"Targeting the EphA4 receptor in the nervous system with biologically active peptides.","volume":"24","author":"Murai","year":"","journal-title":"Mol. Cell. Neurosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.nbd.2012.08.019","article-title":"Defects in neuromuscular junction remodelling in the Smn2B\/- mouse model of spinal muscular atrophy.","volume":"49","author":"Murray","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1093\/hmg\/ddm367","article-title":"Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy.","volume":"17","author":"Murray","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B41","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1038\/nn1653","article-title":"Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF.","volume":"9","author":"Pun","year":"2006","journal-title":"Nat. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S0896-6273(02)00670-0","article-title":"An intrinsic distinction in neuromuscular junction assembly and maintenance in different skeletal muscles.","volume":"34","author":"Pun","year":"2002","journal-title":"Neuron"},{"key":"B43","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.ajhg.2017.01.005","article-title":"Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis.","volume":"100","author":"Riessland","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"B44","doi-asserted-by":"publisher","first-page":"4094","DOI":"10.1093\/hmg\/ddv148","article-title":"Astrocytes influence the severity of spinal muscular atrophy.","volume":"24","author":"Rindt","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"B45","doi-asserted-by":"publisher","first-page":"9920","DOI":"10.1073\/pnas.94.18.9920","article-title":"Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos.","volume":"94","author":"Schrank","year":"1997","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B46","doi-asserted-by":"publisher","first-page":"16347","DOI":"10.1073\/pnas.0706626104","article-title":"2-Chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse.","volume":"104","author":"Shi","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B47","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1093\/hmg\/ddp562","article-title":"Ciliary neurotrophic factor-induced sprouting preserves motor function in a mouse model of mild spinal muscular atrophy.","volume":"19","author":"Simon","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"B48","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.bbagrm.2016.12.008","article-title":"Diverse role of survival motor neuron protein.","volume":"1860","author":"Singh","year":"2017","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"B49","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/gt.2017.52","article-title":"The clinical landscape for SMA in a new therapeutic era.","volume":"24","author":"Talbot","year":"2017","journal-title":"Gene Ther."},{"key":"B50","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.nmd.2012.06.228","article-title":"Dysfunction of the neuromuscular junction in patients with spinal muscular atrophy type 2 and 3.","volume":"22","author":"Van der Pol","year":"2012","journal-title":"Neuromuscul. Disord."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1038\/nm.2901","article-title":"EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.","volume":"18","author":"Van Hoecke","year":"2012","journal-title":"Nat. Med."},{"key":"B52","doi-asserted-by":"publisher","first-page":"4074","DOI":"10.1093\/hmg\/ddt257","article-title":"The D inhibitor RG3039 improves motor functionin SMA mice.","volume":"22","author":"Van Meerbeke","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0092309","article-title":"EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-\u03b2 oligomers.","volume":"9","author":"Vargas","year":"2014","journal-title":"PLoS One"},{"key":"B54","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1006\/geno.1996.4551","article-title":"cDNA isolation, expression, and chromosomal localization of the mouse survival motor neuron gene (Smn).","volume":"40","author":"Viollet","year":"1997","journal-title":"Genomics"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fnins.2019.01233\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T00:24:31Z","timestamp":1574123071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fnins.2019.01233\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,19]]},"references-count":54,"alternative-id":["10.3389\/fnins.2019.01233"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2019.01233","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,19]]},"article-number":"1233"}}