title: Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells.
abstract: Adult mammalian auditory hair cells (HCs) and their associated supporting cells (SCs) do not proliferate, and HC death leads to irreversible neurosensory hearing loss and balance impairment. In nonmammalian vertebrates, loss of HCs induces mitotic proliferation of adjacent nonsensory SCs and/or direct SC transdifferentiation to generate replacement cells. This results in the structural and functional recovery of the nonmammalian sensory systems. Potential replacement of mammalian auditory HCs, either by transplanting cells or by transforming existing cells through molecular therapy, has long been proposed. However, HC replacement strategies with clear therapeutic potential remain elusive. The retinoblastoma (pRB) family of cell cycle regulators, Rb1, Rbl1 (p107), and Rbl2 (p130), regulate the G(1)- to S-phase transition in proliferating cells. In the inner ear, the biochemical and molecular pathways involving pRBs, particularly p107 and p130, are relatively unexplored and their therapeutic suitability is yet to be determined. In this study, we analyzed the cochleae of adult p130 knock-out (p130(-/-)) mice and showed that lack of the p130 gene results in extra rows of HCs and SCs in the more apical regions of the cochlea. No evidence of transdifferentiation of these supernumerary SCs into HCs was observed in the p130(-/-) mouse. Nevertheless, unscheduled proliferation of SCs in the adult p130(-/-) cochlea coupled to downregulation of bona fide cell cycle inhibitors provides a mechanistic basis for the role of p130 as a regulator of SC and HC mitotic quiescence in the more apical regions of the cochlea. Interestingly, p130(-/-) mice exhibited nearly normal peripheral auditory sensitivity.
authors.affiliation: Department of Oral Biology, Creighton University School of Dentistry, Omaha, Nebraska 68178, USA. ssanchez@creighton.edu
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Rocha-Sanchez
authors.forename: Laura R
authors.initials: LR
authors.lastname: Scheetz
authors.forename: Melissa
authors.initials: M
authors.lastname: Contreras
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weston
authors.forename: Megan
authors.initials: M
authors.lastname: Korte
authors.forename: Joann
authors.initials: J
authors.lastname: McGee
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Walsh
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D007758:Ear, Inner / Q000166:cytology* / Q000196:embryology; D004622:Embryo, Mammalian; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006199:Hair Cells, Auditory, Inner / Q000502:physiology*; D047468:Immunoprecipitation; D007760:Labyrinth Supporting Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D017084:Otoacoustic Emissions, Spontaneous / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D017475:Receptors, Nerve Growth Factor; D016160:Retinoblastoma Protein; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C517634:Ngfr protein, mouse; D014404:Tubulin; D009218:Myosins