title: Generation of induced neurons by direct reprogramming in the mammalian cochlea.
abstract: Primary auditory neurons (ANs) in the mammalian cochlea play a critical role in hearing as they transmit auditory information in the form of electrical signals from mechanosensory cochlear hair cells in the inner ear to the brainstem. Their progressive degeneration is associated with disease conditions, excessive noise exposure and aging. Replacement of ANs, which lack the ability to regenerate spontaneously, would have a significant impact on research and advancement in cochlear implants in addition to the amelioration of hearing impairment. The aim of this study was to induce a neuronal phenotype in endogenous non-neural cells in the cochlea, which is the essential organ of hearing. Overexpression of a neurogenic basic helix-loop-helix transcription factor, Ascl1, in the cochlear non-sensory epithelial cells induced neurons at high efficiency at embryonic, postnatal and juvenile stages. Moreover, induced neurons showed typical properties of neuron morphology, gene expression and electrophysiology. Our data indicate that Ascl1 alone or Ascl1 and NeuroD1 is sufficient to reprogram cochlear non-sensory epithelial cells into functional neurons. Generation of neurons from non-neural cells in the cochlea is an important step for the regeneration of ANs in the mature mammalian cochlea.
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada. Electronic address: knishimu@sri.utoronto.ca.
authors.forename: K
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Surgery/Otolaryngology, UCSD School of Medicine, La Jolla, CA 92093, USA. Electronic address: rmacki08@yahoo.com.
authors.forename: R M
authors.initials: RM
authors.lastname: Weichert
authors.affiliation: Department of Cell Biology and Neuroscience, Nelson Laboratories, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA. Electronic address: wenkeliu@rutgers.edu.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Cell Biology and Neuroscience, Nelson Laboratories, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA. Electronic address: rldavis@dls.rutgers.edu.
authors.forename: R L
authors.initials: RL
authors.lastname: Davis
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address: alain.dabdoub@sri.utoronto.ca.
authors.forename: A
authors.initials: A
authors.lastname: Dabdoub
mesh_terms: D000818:Animals; D001306:Auditory Pathways / Q000166:cytology* / Q000502:physiology; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology*; D003051:Cochlea / Q000166:cytology* / Q000502:physiology; D006309:Hearing / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D012038:Regeneration / Q000502:physiology*
keywords: auditory neurons; cochlear non-sensory epithelial cells; hearing; regeneration; reprogramming; spiral ganglion