title: Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds.
abstract: Unlike mammals, birds regenerate auditory hair cells (HCs) after injury. During regeneration, mature non-sensory supporting cells (SCs) leave quiescence and convert into HCs, through non-mitotic or mitotic mechanisms. During embryogenesis, Notch ligands from nascent HCs exert lateral inhibition, restricting HC production. Here, we examined whether Notch signaling (1) is needed in mature birds to maintain the HC/SC pattern in the undamaged auditory epithelium or (2) governs SC behavior once HCs are injured. We show that Notch pathway genes are transcribed in the mature undamaged epithelium, and after HC injury, their transcription is upregulated in the region of highest mitotic activity. In vitro treatment with DAPT, an inhibitor of Notch activity, had no effect on SCs in the undamaged epithelium. Following HC damage, DAPT had no direct effect on SC division. However, after damage, DAPT caused excessive regeneration of HCs at the expense of SCs, through both mitotic and non-mitotic mechanisms. Conversely, overexpression of activated Notch in SCs after damage caused them to maintain their phenotype and inhibited HC regeneration. Therefore, signaling through Notch is not required for SC quiescence in the healthy epithelium or to initiate HC regeneration after damage. Rather, Notch prevents SCs from regenerating excessive HCs after damage.
authors.affiliation: Vertebrate Development Laboratory, Cancer Research UK, London, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Daudet
authors.forename: Robin
authors.initials: R
authors.lastname: Gibson
authors.forename: Jialin
authors.initials: J
authors.lastname: Shang
authors.forename: Amy
authors.initials: A
authors.lastname: Bernard
authors.forename: Julian
authors.initials: J
authors.lastname: Lewis
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stone
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002645:Chickens / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D004848:Epithelium / Q000502:physiology; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000502:physiology; D007760:Labyrinth Supporting Cells / Q000166:cytology / Q000502:physiology; D008938:Mitosis / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases