Notch signaling and Hes labeling in the normal and drug-damaged organ of Corti.
During the development of the inner ear, the Notch cell signaling pathway is responsible for the specification of the pro-sensory domain and influences cell fate decisions. It is assumed that Notch signaling ends during maturity and cannot be reinitiated to alter the fate of new or existing cells in the organ of Corti. This is in contrast to non-mammalian species which reinitiate Delta 1-Notch1 signaling in response to trauma in the auditory epithelium, resulting in hair cell regeneration through transdifferentiation and/or mitosis. We report immunohistochemical data and Western protein analysis showing that in the aminoglycoside-damaged guinea pig organ of Corti, there is an increase in proteins involved in Notch activation occurring within 24h of a chemical hair cell lesion. The signaling response is characterized by the increased presence of Jagged1 ligand in pillar and Deiters cells, Notch1 signal in surviving supporting cell nuclei, and the absence of Jagged2 and Delta-like1. The pro-sensory bHLH protein Atoh1 was absent at all time points following an ototoxic lesion, while the repressor bHLH transcription factors Hes1 and Hes5 were detected in surviving supporting cell nuclei in the former inner and outer hair cell areas, respectively. Notch pathway proteins peaked at 2 weeks, decreased at 1 month, and nearly disappeared by 2 months. These results indicate that the mammalian auditory epithelium retains the ability to regulate Notch signaling and Notch-dependent Hes activity in response to cellular trauma and that the signaling is transient. Additionally, since Hes activity antagonizes the transcription of pro-sensory Atoh1, the presence of Hes after a lesion may prohibit the occurrence of transdifferentiation in the surviving supporting cells.
Batts
Shelley A
SA
Kresge Hearing Research Institute, University of Michigan Medical School, MSRB-3, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5648, USA.
Shoemaker
Christopher R
CR
Raphael
Yehoash
Y
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002470:Cell Survival; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007612:Kanamycin / Q000633:toxicity; D008297:Male; D018613:Microscopy, Confocal; D009925:Organ of Corti / Q000166:cytology / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
D051792:Basic Helix-Loop-Helix Proteins; D007612:Kanamycin; D051880:Receptors, Notch