PLoS One
| Autor: | María Rodríguez Aburto, Isabel Varela-Nieto, Ulf R. Rapp, Carmen Muñoz-Agudo, Hortensia Sánchez-Calderón, Marta Magariños |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Cycle regulation
Pyridines Cellular differentiation medicine.medical_treatment lcsh:Medicine Chick Embryo Cell Biology/Cell Signaling Nerve growth-factor Insulin-Like Growth Factor I Phosphorylation lcsh:Science Neurons Multidisciplinary Kinase Stem Cells Benzenesulfonates Cell Differentiation Cell Biology/Cellular Death and Stress Responses Sorafenib Neuroscience/Neurodevelopment Cell biology Mitogen-activated protein kinase raf Kinases Research Article Otolaryngology/Audiology Niacinamide Subcellular-localization Cell Biology/Neuronal Signaling Mechanisms B-raf Cell Biology/Developmental Molecular Mechanisms C-raf-1 gene Biology Models Biological Gene Expression Regulation Enzymologic ddc:570 Neuroscience/Neuronal Signaling Mechanisms medicine Transcription factors Animals Progenitor cell Protein Kinase Inhibitors Transcription factor Cell Proliferation Cell growth Phenylurea Compounds Growth factor lcsh:R Epithelial Cells Developmental Biology/Neurodevelopment Ear Inner Developmental Biology/Cell Differentiation biology.protein lcsh:Q sense organs |
| Zdroj: | PLoS ONE, Vol 5, Iss 12, p e14435 (2010) PLoS ONE Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1932-6203 |
| Popis: | [Background]: Early inner ear development requires the strict regulation of cell proliferation, survival, migration and differentiation, coordinated by the concerted action of extrinsic and intrinsic factors. Deregulation of these processes is associated with embryonic malformations and deafness. We have shown that insulin-like growth factor I (IGF-I) plays a key role in embryonic and postnatal otic development by triggering the activation of intracellular lipid and protein kinases. RAF kinases are serine/threonine kinases that regulate the highly conserved RAS-RAF-MEK-ERK signaling cascade involved in transducing the signals from extracellular growth factors to the nucleus. However, the regulation of RAF kinase activity by growth factors during development is complex and still not fully understood. [Methodology/Principal Findings]: By using a combination of qRT-PCR, Western blotting, immunohistochemistry and in situ hybridization, we show that C-RAF and B-RAF are expressed during the early development of the chicken inner ear in specific spatiotemporal patterns. Moreover, later in development B-RAF expression is associated to hair cells in the sensory patches. Experiments in ex vivo cultures of otic vesicle explants demonstrate that the influence of IGF-I on proliferation but not survival depends on RAF kinase activating the MEK-ERK phosphorylation cascade. With the specific RAF inhibitor Sorafenib, we show that blocking RAF activity in organotypic cultures increases apoptosis and diminishes the rate of cell proliferation in the otic epithelia, as well as severely impairing neurogenesis of the acoustic-vestibular ganglion (AVG) and neuron maturation. [Conclusions/Significance]: We conclude that RAF kinase activity is essential to establish the balance between cell proliferation and death in neuroepithelial otic precursors, and for otic neuron differentiation and axonal growth at the AVG. This work was supported by the Integrated Action HA2004-0096 to IVN and URR, Ministerio de Ciencia e Innovacion (SAF2008-00470) and Fundacion Mutua Madrileña to IVN. María R. Aburto and Hortensia Sánchez-Calderón hold contracts from Consejo Superior de Investigaciones Cientificas-FSE I3. |
| Databáze: | OpenAIRE |
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