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 G1- 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 p-/-130 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.
| Original language | English |
|---|---|
| Pages (from-to) | 8883-8893 |
| Number of pages | 11 |
| Journal | Journal of Neuroscience |
| Volume | 31 |
| Issue number | 24 |
| DOIs | |
| State | Published - Jun 15 2011 |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
Cite this
Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells. / Rocha-Sanchez, Sonia; Scheetz, Laura R.; Contreras, Melissa; Weston, Michael; Korte, Megan; McGee, JoAnn; Walsh, Edward J.
In: Journal of Neuroscience, Vol. 31, No. 24, 15.06.2011, p. 8883-8893.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells
AU - Rocha-Sanchez, Sonia
AU - Scheetz, Laura R.
AU - Contreras, Melissa
AU - Weston, Michael
AU - Korte, Megan
AU - McGee, JoAnn
AU - Walsh, Edward J.
PY - 2011/6/15
Y1 - 2011/6/15
N2 - 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 G1- 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 p-/-130 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.
AB - 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 G1- 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 p-/-130 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.
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U2 - 10.1523/JNEUROSCI.5821-10.2011
DO - 10.1523/JNEUROSCI.5821-10.2011
M3 - Article
VL - 31
SP - 8883
EP - 8893
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 24
ER -