Pharmacological inhibition of Notch signaling in the mature guinea pig cochlea.
Recent studies using explant cultures have demonstrated that pharmacological inhibition of Notch signaling by gamma-secretase inhibitors generates supernumerary hair cells in embryonic or neonatal cochleae. The aim of this study was to examine the effects of such pharmacological inhibition on mature auditory epithelia in vivo. Normal adult guinea pig auditory epithelia exhibited weak or no immunoreactivity for Notch1 and Jagged1, whereas ototoxic treatment caused the upregulation of these molecules in damaged auditory epithelia. Local application of a gamma-secretase inhibitor in damaged cochleae generated ectopic hair cells in mature auditory epithelia. These findings indicate that pharmacological inhibition of Notch signaling is a possible strategy for hair cell regeneration in adult auditory epithelia.
Hori
Ryusuke
R
Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nakagawa
Takayuki
T
Sakamoto
Tatsunori
T
Matsuoka
Yoshinori
Y
Takebayashi
Shinji
S
Ito
Juichi
J
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000378:metabolism* / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007612:Kanamycin; D008565:Membrane Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology; D009498:Neurotoxins; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D002135:Calcium-Binding Proteins; D004151:Dipeptides; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009498:Neurotoxins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D007612:Kanamycin; D053829:Amyloid Precursor Protein Secretases; C058076:calpain inhibitor III