caa a22 4500 606175202 CHVBK 20210128100742.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00018-015-1919-x doi (NATIONALLICENCE)springer-10.1007/s00018-015-1919-x C - Raf deficiency leads to hearing loss and increased noise susceptibility [Elektronische Daten] [Rocío de Iriarte Rodríguez, Marta Magariños, Verena Pfeiffer, Ulf Rapp, Isabel Varela-Nieto] 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. The Author(s), 2015 Programmed cell death nationallicence ERK nationallicence FoxG1 nationallicence Inflammation nationallicence NIHL nationallicence Otic nationallicence de Iriarte Rodríguez Rocío Instituto de Investigaciones Biomédicas "Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain aut Magariños Marta Instituto de Investigaciones Biomédicas "Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain aut Pfeiffer Verena Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, Versbacher Strasse 5, 97078, Würzburg, Germany aut Rapp Ulf Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, Versbacher Strasse 5, 97078, Würzburg, Germany aut Varela-Nieto Isabel Instituto de Investigaciones Biomédicas "Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain aut Cellular and Molecular Life Sciences Springer Basel 72/20(2015-10-01), 3983-3998 1420-682X 72:20<3983 2015 72 18 https://doi.org/10.1007/s00018-015-1919-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1919-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- de Iriarte Rodríguez Rocío Instituto de Investigaciones Biomédicas "Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain aut NATIONALLICENCE 700 1- Magariños Marta Instituto de Investigaciones Biomédicas "Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain aut NATIONALLICENCE 700 1- Pfeiffer Verena Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, Versbacher Strasse 5, 97078, Würzburg, Germany aut NATIONALLICENCE 700 1- Rapp Ulf Institute for Medical Radiation and Cell Research (MSZ), University of Würzburg, Versbacher Strasse 5, 97078, Würzburg, Germany aut NATIONALLICENCE 700 1- Varela-Nieto Isabel Instituto de Investigaciones Biomédicas "Alberto Sols”, CSIC-UAM, Arturo Duperier 4, 28029, Madrid, Spain aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/20(2015-10-01), 3983-3998 1420-682X 72:20<3983 2015 72 18