BUSCADOR RECOLECTA

Digital.CSIC. Repositorio Institucional del CSIC

oai:digital.csic.es:10261/208458

Trabajo presentado en el 56th Inner Ear Biology Workshop, celebrado en Padua (Italia) del 7 al 10 de septiembre de 2019., In all vertebrates, the inner ear originates from the otic placode, an ectodermal patch in the head which invaginates and closes to form the otic vesicle (OV) or otocyst. The OV is considered the anlagen of the inner ear since their epithelial cells will differentiate generating most of the cell types building the complex structure of the adult inner ear. This transition is carried out by spatio-temporal restricted processes of proliferation, differentiation, migration, apoptosis, autophagy and senescence. A network of intracellular signals manages the precise process of development. The knowledge of the molecular bases that guide otic development is necessary for the design of novel treatments for the protection and repair of cells in hearing loss disorders. One of the emerging family of compounds with critical roles in most cell biological processes are the bioactive sphingolipids. In fact the term ¿morphogenetic lipids¿ are coined for sphingolipids that regulate stem cells survival and differentiation during embryonic and postnatal development. Ceramide is the central backbone precursor of all complex bioactive sphingolipids. We had previously shown that a synthetic short-chain ceramide analogue was a potent inductor of apoptosis in OV cultures. The action of ceramide is finished by its phosphorylation to ceramide-1-phosphate (C1P), a reaction catalysed by the ceramide kinase (CERK). The presence of CERK has not been studied in the OV. In the chicken embryo, Insulin-like growth factor-1 (IGF-1) is required for the survival and differentiation of the epithelial auditory precursors. In addition, IGF-1 deficit causes syndromic deafness in mice and men. In this work we have studied whether the pro-survival role of IGF-1 are due to the generation of C1P. To tackle the study we have used a specific CERK inhibitor (NVP-231). We have addressed the study in ex vivo cultures of OVs described as a good model of inner ear development that mimics the in vivo program maintaining the morphogenetic spatiotemporal pattern. Our results show that CERK is expressed during the developing inner ear in chicken. The inhibition of CERK reduced proliferation and increased cell cycle arrest followed by cell death. The inhibition of CERK also altered the neurogenesis in the acoustic vestibular ganglion (AVG). Taken together, these results would confirm the involvement of C1P in the morphogenesis of the OV and AVG. The inhibitor counteracted the effect of IGF-1 exogenously added, suggesting that a part of the IGF-1 protective role could be carried out by CERK stimulation and C1P production., This work was supported by Spanish Ministerio de Economía, Industria y Competitividad (SAF2017-86107-R-FEDER) to MM and IVN.