title: Netrin 1 mediates protective effects exerted by insulin-like growth factor 1 on cochlear hair cells.
abstract: Sensorineural hearing loss (SNHL) is mainly caused by the damage of cochlear hair cells (HCs). As HCs and supporting cells (SCs) do not proliferate in postnatal mammals, the loss of HCs and SCs is irreversible, emphasizing the importance of preserving their numbers to prevent SNHL. It is known that insulin-like growth factor 1 (IGF1) is instrumental in the treatment of SNHL. Our previous study indicates that IGF1 protects HCs against aminoglycoside by activating IGF1 receptor and its two major downstream pathways, PI3K/AKT and MEK/ERK, in SCs, which results in the upregulation of the expression of the Netrin1-encoding gene (Ntn1). However, the mechanisms underlying IGF1-induced protection of HCs via SC activation as well as the role of NTN1 in this process have not been elucidated. Here, we demonstrated that NTN1, similar to IGF1, promoted HC survival. NTN1 blocking antibody attenuated IGF1-induced HC protection from aminoglycoside, indicating that NTN1 is the effector molecule of IGF1 signaling during HC protection. In situ hybridization demonstrated that IGF1 potently induced Ntn1 expression in SCs. NTN1 receptors were abundantly expressed in the cochlea; among them, UNC5B mediated IGF1 protective effects on HCs, as NTN1 binding to UNC5B inhibited HC apoptosis. These results provide new insights into the mechanisms underlying IGF1 protection of cochlear HCs, suggesting a possibility of using NTN1 as a new treatment for SNHL.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamahara
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Shiga Medical Center Research Institute, Moriyama, Shiga 524-8523, Japan.
authors.forename: Juichi
authors.initials: J
authors.lastname: Ito
authors.affiliation: Shiga Medical Center Research Institute, Moriyama, Shiga 524-8523, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Omori
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan. Electronic address: yamamoto@ent.kuhp.kyoto-u.ac.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D003051:Cochlea / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects*; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009355:Neomycin / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000906:Antibodies; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D053148:Caspase 3; D009355:Neomycin
keywords: Aphidicolin (PubChem CID: 457964); Apoptosis; Effector molecules; Insulin-like growth factor 1; LY294002 (PubChem CID: 3973); Netrin 1; Sensorineural hearing loss; Supporting cells; U0126 (PubChem CID: 3006531)