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Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas

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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 γ-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.

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Acknowledgements

We thank Dr. Hua Han for creating RBP-J f/f mice; Dr. Izumu Saito for adenovirus vector (AxCANCre); Dr. Tama Hasson for anti-Myosin7a antibodies; Dr. Jane Johnson for anti-Math1 antibodies; and Ms. Yasuko Doi, Ms. Mikiyo Nakata, Ms. Youko Sasaki, and Ms. Takae Toyoshima for excellent technical assistance. This study was supported by a Center of Excellence grant and Regenerative medicine realization project grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Research on Measures for Intractable Diseases, Health and Labour Sciences Research Grant from Ministry of Health Labour and Welfare of Japan.

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Authors and Affiliations

  1. Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Norio Yamamoto, Masayuki Tsuji, Daisuke Yabe & Tasuku Honjo

  2. Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Norio Yamamoto & Juichi Ito

  3. Research Institute, Shiga Medical Center, Moriyama, 524-8524, Japan

    Kenji Tanigaki

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  1. Norio Yamamoto
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  2. Kenji Tanigaki
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  3. Masayuki Tsuji
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  4. Daisuke Yabe
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  5. Juichi Ito
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  6. Tasuku Honjo
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Correspondence to Tasuku Honjo.

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N. Yamamoto and K. Tanigaki contributed equally to this work

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Yamamoto, N., Tanigaki, K., Tsuji, M. et al. Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas. J Mol Med 84, 37–45 (2006). https://doi.org/10.1007/s00109-005-0706-9

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  • DOI: https://doi.org/10.1007/s00109-005-0706-9

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