title: Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death.
abstract: Although cardio-vascular incidents and sudden cardiac death (SCD) are among the leading causes of premature death in the general population, the origins remain unidentified in many cases. Genome-wide association studies have identified Meis1 as a risk factor for SCD. We report that Meis1 inactivation in the mouse neural crest leads to an altered sympatho-vagal regulation of cardiac rhythmicity in adults characterized by a chronotropic incompetence and cardiac conduction defects, thus increasing the susceptibility to SCD. We demonstrated that Meis1 is a major regulator of sympathetic target-field innervation and that Meis1 deficient sympathetic neurons die by apoptosis from early embryonic stages to perinatal stages. In addition, we showed that Meis1 regulates the transcription of key molecules necessary for the endosomal machinery. Accordingly, the traffic of Rab5(+) endosomes is severely altered in Meis1-inactivated sympathetic neurons. These results suggest that Meis1 interacts with various trophic factors signaling pathways during postmitotic neurons differentiation.
authors: Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France.
authors: Fabrice
authors: F
authors: Bouilloux
authors: Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France.
authors: Jérôme
authors: J
authors: Thireau
authors: Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France.
authors: Stéphanie
authors: S
authors: Ventéo
authors: Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France.
authors: Charlotte
authors: C
authors: Farah
authors: Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France.
authors: Sarah
authors: S
authors: Karam
authors: Sleep Unit, Department of Neurology, Gui-de-Chauliac hospital, Montpellier, France.
authors: Yves
authors: Y
authors: Dauvilliers
authors: Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France.
authors: Jean
authors: J
authors: Valmier
authors: Cancer Research Program, The Methodist Hospital Research Institute, Houston, United States.
authors: Neal G
authors: NG
authors: Copeland
authors: Cancer Research Program, The Methodist Hospital Research Institute, Houston, United States.
authors: Nancy A
authors: NA
authors: Jenkins
authors: Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France.
authors: Sylvain
authors: S
authors: Richard
authors: Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France.
authors: Frédéric
authors: http://orcid.org/0000-0002-0515-7483
authors: F
authors: Marmigère
mesh_terms: D000818:Animals; D017209:Apoptosis; D001342:Autonomic Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D016757:Death, Sudden, Cardiac; D011992:Endosomes / Q000378:metabolism; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000172:deficiency*
chemical_list: D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins
keywords: Homeodomain; arrhythmia; cardiac conduction; cell biology; clathrin; developmental biology; endocytosis; mouse; neurotrophin; stem cells