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© 2021 by the authors., Insulin-like growth factor 1 (IGF-1) is a peptide hormone belonging to the insulin family of proteins. Almost all of the biological effects of IGF-1 are mediated through binding to its high-affinity tyrosine kinase receptor (IGF1R), a transmembrane receptor belonging to the insulin receptor family. Factors, receptors and IGF-binding proteins form the IGF system, which has multiple roles in mammalian development, adult tissue homeostasis, and aging. Consequently, mutations in genes of the IGF system, including downstream intracellular targets, underlie multiple common pathologies and are associated with multiple rare human diseases. Here we review the contribution of the IGF system to our understanding of the molecular and genetic basis of human hearing loss by describing, (i) the expression patterns of the IGF system in the mammalian inner ear; (ii) downstream signaling of IGF-1 in the hearing organ; (iii) mouse mutations in the IGF system, including upstream regulators and downstream targets of IGF-1 that inform cochlear pathophysiology; and (iv) human mutations in these genes causing hearing loss., This research was funded by Spanish FEDER/CM, B2017/BMD-3688; FEDER/MICIN, PID2020-115274RB-I00-THEARPY and EU H2020-INTERREG, 0551_PSL_6_E grants to I.V.-N. and ACCI/ISCIII, ER19P5AC761 grant to L.R.-d.l.R. Á.G.-M. holds a FPU (FPU16/03308; MECD) contract. S.M.-C. and L.R.-d.l.R. hold CIBER ISCIII researcher contracts.

Table of contents: zip file containing 7 folders: Figure 2 folder [Figure 2_Blots Report.pdf; Figure_2C_qPCR.xlsx; Figure_2D_qPCR.xlsx; Figure_2E&G_Data&Analysis.xlsx; Figure_2F_Data&Analysis.xlsx] Figure 3 folder [Figure 3_Blots Report.pdf; Figure_3B_Data&Analysis.xlsx; Figure_3C_Data&Analysis.xlsx] Figure 4 folder [Figure 4_Blots Report.pdf;Figure_4A_Data&Analysis.xlsx; Figure_4B_Data&Analysis.xlsx; Figure_4C&D_Data&Analysis.xlsx] Figure 5 folder [Figure 5_Blots Report.pdf; Figure_5A_Data&Analysis.xlsx; Figure_5B_Data&Analysis.xlsx; Figure_5C-D_Data&Analysis.xlsx; Figure_5E-F_Data&Analysis.xlsx] Figure 6 folder [Figure 6_Blots Report.pdf; Figure_6B_Data&Analysis.xlsx; Figure_6C_Data&Analysis.xlsx; Figure_6D_Data&Analysis.xlsx] Figure 7 folder [Figure 7_Blots Report.pdf; Figure_7B_Oxyblot_Data&Analysis.xlsx; Figure_7B_qPCR_Data&Analysis.xlsx; Figure_7B_WesternBlotting_Data&Analysis.xlsx; Figure_7C_Data&Analysis.xlsx; Figure_7D_Data&Analysis.xlsx; Figure_7E_Data&Analysis.xlsx] Supplementary Material folder [Figure_S2_Data&Analysis.xlsx], MCIN/AEI/10.13039/ 501100011033 THEARPY-PID2020-115274RB-I00; 0551_PSL_6_E POCTEP FGCSIC/ PSL-INTERREG/FEDER NITROPROHEAR, Peer reviewed

The current Research Topic tries to highlight some of the most relevant recent advances regarding sensorineural hearing loss (SNHL). The etiology of SNHL primarily involves hereditary factors, ototoxic drugs, noise, and aging, all of which trigger two main mechanisms: damage to the organ of Corti, namely mechanosensory hair cells (HCs) and non-sensory supporting cells (SCs), and/or loss of spiral ganglion neurons (SGNs) that subsequently form the auditory nerve and hence connect the inner ear to the brain., TJ was supported by the NIH/NIDCD (K08DC019683). IV-N was supported by PID2020-115274RB-I00 from the Spanish MCIN/AEI/10.13039/501100011033 and FEDER.

Cellular senescence is a stable anti-proliferative state, which has an essential role in cell balance control in diverse physiological and pathological settings (Chan and Narita, 2019; Gorgoulis et al., 2019). Senescence research is a highly dynamic field that has experienced a radical expansion over the last few years with the identification of the role of senescence in a growing list of diseases and physiological processes and the promise for therapeutic interventions based on senescence (Munoz-Espin and Serrano, 2014; Paez-Ribes et al., 2019). The current Research Topic aims to give an overview of the latest advances in this field highlighting the progress in understanding the mechanism of senescence and its link to disease in the nervous system and other organs. The issue includes a wide range of articles, including original research reports, mini-reviews, and reviews that explore diverse angles of this topic, showcasing the current trends in senescence research., Research in the authors’ laboratories was supported by the following grants: RTI2018-098520-B-I00 from the Spanish MCIN/AEI/10.13039/501100011033 and FEDER to IP. 2020ΣE01300001 from the Ministry of Development and Investment, 775 (Hippo) and 3782 (PACOREL) from the Hellenic Foundation for Research and Innovation, 70/3/8916 from NKUA-SARG, the Welfare Foundation for Social & Cultural Sciences (KIKPE), and H. Pappas donation to VG, PID2020-115274RB-I00 from the Spanish MCIN/AEI/10.13039/501100011033 and FEDER to IV-N. IP and IV-N were members of the Spanish Senescence Network, Senestherapy (RED2018-102698-T).

Trabajo presentado en el Spanish Symposium on IGFs and Insulin 2022: Implications in Physiology and Disease, celebrado en Logroño (España) del 21 al 22 de abril de 2022., Human deficiency of insulin-like growth factor type 1 (IGF-1) causes a rare disorder (OMIM608747; ORPHA73272), which leads to sensorineural hearing loss and neurological disorders [1,2]. The Igf1-deficient mouse replicates this neurological phenotype syndrome, and shows impaired neuronal differentiation and increased apoptosis of auditory neurons [3,4]. IGF-1 is a hormone associated with decreased neuroinflammation [5] and increased cellular senescence, though molecular mechanisms involved are poorly understood [6]. In order to study IGF-1 deficiency and understand the alterations linked to neuronal loss, a cellular model of the human disease was generated in the murine neuroblastoma cell line N2a by using CRISPR/Cas9 technology. The crRNA:tracrRNA:Cas9 complex was transfected as a ribonucleoprotein and clones were isolated by limiting dilution. Sanger and next-generation sequencing confirmed Igf1 gene editing. Clones 4A10 and 2G3, with a mutation frequency above 90%, were selected for the study. Both clones, which differentially expressed IGF system factors and proinflammatory cytokines, showed alterations in bleomycin-induced senescence and increased resistance to cisplatin treatment. Chronic IGF-1 deficiency leads to changes in the response to ototoxic drugs such as cisplatin and bleomycin in neuroblastoma cells. These cell lines are an opportunity to unravel new molecular mechanisms of neuronal damage associated with chronic IGF1 deficiency., THEARPY-PID2020-115274RB-I00 funded by MCIN/AEI/10.13039/501100011033 and NITROPROHEAR (0551_PSL_6_E POCTEP FGCSIC/PSL-INTERREG/FEDER).

Insulin-like growth factor 1 (IGF-1) is a trophic factor for the nervous system where it exerts pleiotropic effects, including the regulation of metabolic homeostasis. IGF-1 deficiency induces morphological alterations in the cochlea, apoptosis and hearing loss. While multiple studies have addressed the role of IGF-1 in hearing protection, its potential function in the modulation of otic metabolism remains unclear. Here, we report that “House Ear Institute-organ of Corti 1” (HEI-OC1) auditory cells express IGF-system genes that are regulated during their differentiation. Upon binding to its high-affinity receptor IGF1R, IGF-1 activates AKT and mTOR signaling to stimulate anabolism and, concomitantly, to reduce autophagic catabolism in HEI-OC1 progenitor cells. Notably, IGF-1 stimulation during HEI-OC1 differentiation to mature otic cells sustained both constructive metabolism and autophagic flux, possibly to favor cell remodeling. IGF1R engagement and downstream AKT signaling promoted HEI-OC1 cell survival by maintaining redox balance, even when cells were challenged with the ototoxic agent cisplatin. Our findings establish that IGF-1 not only serves an important function in otic metabolic homeostasis but also activates antioxidant defense mechanisms to promote hair cell survival during the stress response to insults., This research was funded by Spanish MCIN/AEI/10.13039/501100011033 THEARPYPID2020-115274RB-I00; 0551_PSL_6_E POCTEP FGCSIC/ PSL-INTERREG/FEDER NITROPROHEAR and CA20121 COST Action/EU—BenBedPhar grants to I.V.-N. Á.G.-M. holds an FPU (FPU16/03308; MECD) fellowship, and L.R.-d.l.R. holds a CIBER ISCIII researcher contract., Peer reviewed