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dc.contributor.authorSalminen, Aaro V.
dc.contributor.authorGarrett, Lillian
dc.contributor.authorSchormair, Barbara
dc.contributor.authorRozman, Jan
dc.contributor.authorGiesert, Florian
dc.contributor.authorNiedermeier, Kristina M.
dc.contributor.authorBecker, Lore
dc.contributor.authorRathkolb, Birgit
dc.contributor.authorRacz, Ildiko
dc.contributor.authorKlingenspor, Martin
dc.contributor.authorKlopstock, Thomas
dc.contributor.authorWolf, Eckhard
dc.contributor.authorZimmer, Andreas
dc.contributor.authorGailus-Durner, Valerie
dc.contributor.authorTorres, Miguel 
dc.contributor.authorFuchs, Helmut.
dc.contributor.authorHrabe de Angelis, Martin
dc.contributor.authorWurst, Wolfgang
dc.contributor.authorHoelter, Sabine M
dc.contributor.authorWinkelmann, Juliane
dc.date.accessioned2018-10-19T08:00:44Z
dc.date.available2018-10-19T08:00:44Z
dc.date.issued2017
dc.identifierISI:000406796600005
dc.identifier.citationDis Model Mech. 2017; 10(8):981-991
dc.identifier.issn1754-8403
dc.identifier.urihttp://hdl.handle.net/20.500.12105/6500
dc.description.abstractMEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals. We used heterozygous Meis1-knockout mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability, and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, which is compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it.
dc.description.sponsorshipA.V.S. was supported by the Emil Aaltonen Foundation, Tampere, Finland (Emil Aaltosen Saatio). J.W. and M.T. were partly funded by the European Commission through an ERA-NET NEURON grant. This work has been funded by the German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung) to the GMC (Infrafrontier grant 01KX1012), to the German Center for Diabetes Research (DZD e.V.) and through the Integrated Network MitoPD (Mitochondrial endophenotypes of Morbus Parkinson), under the auspices of the e:Med Programme (grant 031A430E), as well as by the Helmholtz Portfolio Theme `Supercomputing and Modelling for the Human Brain' (SMHB) to W.W. This work was also supported by the German Science Foundation Collaborative Research Centre (CRC) (Deutsche Forschungsgemeinschaft) 870.
dc.language.isoeng
dc.publisherThe Company of Biologists 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectMeis1
dc.subjectPrepulse inhibition
dc.subjectRestless legs syndrome
dc.subjectSensorimotor system
dc.subjectMouse model
dc.subjectPramipexole
dc.subjectRESTLESS LEGS SYNDROME
dc.subjectGENOME-WIDE ASSOCIATION
dc.subjectPREPULSE INHIBITION
dc.subjectEXPRESSION LEVELS
dc.subjectRISK
dc.subjectGENES
dc.subjectSLEEP
dc.subjectPATHOPHYSIOLOGY
dc.subjectHOMEOPROTEINS
dc.subjectNEUROGENESIS
dc.titleMeis1: effects on motor phenotypes and the sensorimotor system in mice
dc.typejournal article
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID28645892
dc.format.volume10
dc.format.page981-991
dc.identifier.doi10.1242/dmm.030080
dc.contributor.funderEmil Aaltosen Säätiö (Finlandia) 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderFederal Ministry of Education & Research (Alemania) 
dc.contributor.funderDeutsche Forschungsgemeinschaft (Alemania) 
dc.description.peerreviewed
dc.identifier.e-issn1754-8411
dc.relation.publisherversionhttps://doi.org/10.1242/dmm.030080
dc.identifier.journalDisease Models and Mechanisms
dc.repisalud.orgCNICCNIC::Grupos de investigación::Control Genético del Desarrollo y Regeneración de Órganos
dc.repisalud.institucionCNIC
dc.rights.accessRightsopen accesses_ES


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Atribución 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Atribución 4.0 Internacional