Insulin-like growth factor-1 regulates survival and differentiation in otic cells

Trabajo presentado en el 6th Symposium on Biomedical Research "Advances and Perspectives in Molecular Endocrinology", celebrado en Madrid (España) el 31 de mayo de 2019.Insulin-like growth factor-1 (IGF-1) is a key element in chicken otic development, and its deficit causes syndromic deafness in mice and men (1). Early steps of inner ear development involve the formation of an autonomous embryonic structure, the otic vesicle or otocyst. Otic vesicle development requires the coordinated actions of apoptosis, proliferation, senescence, cell differentiation and autophagy (2). Autophagy is a catabolic process essential for vertebrate development and homeostasis. We have reported that autophagy is required to facilitate the clearance of apoptotic cells and neuronal differentiation during early otic development (3). In other cellular context, IGF-1 has been shown to regulate autophagy (4). To better understand the molecular actions of IGF-1 and its potential modulation of autophagy in otic cells, we have used the cell line HEI-OC1 (derived from the auditory organ of the transgenic mouse Immortomouse¿) and ex vivo cultures of chicken otocysts. IGF-1 signaling pathway was studied by Western blotting of main IGF-1 targets. Proliferation was measured by incorporation of EdU. Apoptosis was assessed by TUNEL labelling and flow cytometry. Autophagy flux was analyzed by measuring LC3 and p62 relative protein levels. Our results show that IGF-1 promotes cell survival and cell proliferation while reduces cell death in both experimental models. IGF-1 is also playing a role in neuronal differentiation in the otic vesicle, maintaining otic neuroblasts in an undifferentiated and proliferative state. Furthermore IGF-1 actions include the downregulation of autophagy, which is induced in response to starvation and is essential for development and differentiation of otic cells.This work was supported by FEDER/SAF2017-86107-R-HEARCODE. SP holds an FPI predoctoral fellowship (BES-2015- 071311; European Social Fund/MINECO). AGM holds a MECD FPU fellowship (FPU16/03308). LR-R holds a contract supported by CIBERER (Institute of Health Carlos III) co-financed with FEDER fund