title: Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas.
abstract: Mammalian inner ear hair cells in cochleas are believed to be incapable of regeneration after birth, which hampers treatment of sensorineural hearing impairment mainly caused by hair cell loss. Sensory epithelia of cochleas are composed of hair cells and supporting cells, both of which originate from common progenitors. Notch/RBP-J signaling is an evolutionally conserved pathway involved in specification of various cell types in developmental stage and even in some of postnatal mammalian organs. The specification of hair cell fate from the progenitors is inhibited by Notch/RBP-J signaling in embryonic inner ears. However, its function in postnatal inner ears is unknown. We showed that inhibition of Notch/RBP-J signaling, by either conditional disruption of the Rbpsuh gene or treatment with a gamma-secretase inhibitor, could give rise to ectopic hair cells in the supporting cell region in organs of Corti from neonatal mouse cochleas where hair cells have not been considered to regenerate after birth. We also showed that down-regulation of Hes5 and up-regulation of Math1 were associated with ectopic hair cell induction. These results suggest that Notch/RBP-J signaling inhibits supporting cells from differentiation into hair cells even in postnatal days, implying that inhibitors of Notch/RBP-J signaling can be used to help regenerating hair cells after birth and thus serve for potential treatment of intractable sensorineural hearing impairment caused by hair cell loss without genetical manipulation.
authors.affiliation: Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Tanigaki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuji
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yabe
authors.forename: Juichi
authors.initials: J
authors.lastname: Ito
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D003051:Cochlea / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D004398:Dyneins / Q000378:metabolism; D004627:Embryonic Induction; D006198:Hair Cells, Auditory / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004398:Dyneins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D000081412:Myosin VIIa; D009218:Myosins; D051880:Receptors, Notch; D012097:Repressor Proteins; C500943:Atoh1 protein, mouse; C489685:Hes5 protein, mouse; C000631456:Myo7a protein, mouse; C497571:Rbpj protein, mouse