title: C-Raf deficiency leads to hearing loss and increased noise susceptibility.
abstract: The family of RAF kinases transduces extracellular information to the nucleus, and their activation is crucial for cellular regulation on many levels, ranging from embryonic development to carcinogenesis. B-RAF and C-RAF modulate neurogenesis and neuritogenesis during chicken inner ear development. C-RAF deficiency in humans is associated with deafness in the rare genetic insulin-like growth factor 1 (IGF-1), Noonan and Leopard syndromes. In this study, we show that RAF kinases are expressed in the developing inner ear and in adult mouse cochlea. A homozygous C-Raf deletion in mice caused profound deafness with no evident cellular aberrations except for a remarkable reduction of the K(+) channel Kir4.1 expression, a trait that suffices as a cause of deafness. To explore the role of C-Raf in cellular protection and repair, heterozygous C-Raf (+/-) mice were exposed to noise. A reduced C-RAF level negatively affected hearing preservation in response to noise through mechanisms involving the activation of JNK and an exacerbated apoptotic response. Taken together, these results strongly support a role for C-RAF in hearing protection.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain.|Centre for Biomedical Network Research (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: de Iriarte Rodríguez
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain. mmagarinos@iib.uam.es.|Centre for Biomedical Network Research (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain. mmagarinos@iib.uam.es.|Departamento de Biología, Universidad Autónoma de Madrid, Darwin 2, 28049, Madrid, Spain. mmagarinos@iib.uam.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Magariños
authors.affiliation: Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, Versbacher Strasse 5, 97078, Würzburg, Germany.|Institute for Anatomy and Cell Biology, University of Würzburg, Koellikerstraße 6, 97070, Würzburg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Pfeiffer
authors.affiliation: Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, Versbacher Strasse 5, 97078, Würzburg, Germany.|Molecular Mechanisms of Lung Cancer, Max Planck Institute for Heart and Lung Research, Parkstr. 1, 61231, Bad Nauheim, Germany.
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain.|Centre for Biomedical Network Research (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain.|Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Varela-Nieto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003051:Cochlea / Q000378:metabolism; D007758:Ear, Inner / Q000196:embryology / Q000378:metabolism*; D005260:Female; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009622:Noise; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019908:Proto-Oncogene Proteins c-raf
keywords: ERK; FoxG1; Inflammation; NIHL; Otic; Programmed cell death