Cell cycle regulation in the inner ear sensory epithelia: Role of cyclin D1 and cyclin-dependent kinase inhibitors

Laine, Heidi; Sulg, Marilin; Kirjavainen, Anna; Pirvola, Ulla

doi:10.1016/j.ydbio.2009.10.027

Cited by 66 publications

(78 citation statements)

References 40 publications

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“…3S). Furthermore, LIN28B overexpression significantly increased the expression of the let-7 targets N-Myc (Mycn) and Cyclin D1 (ccnd1) (45,46), which have been shown to positively regulate prosensory cell proliferation in the murine cochleae and vestibular organs (47)(48)(49) (Fig. 3S).…”

Section: Lin28b Overexpression Results In a Delay In Prosensory Cell mentioning

confidence: 98%

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

Golden

Benito-Gonzalez

Doetzlhofer

2015

Proc. Natl. Acad. Sci. U.S.A.

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Proper tissue development requires strict coordination of proliferation, growth, and differentiation. Strict coordination is particularly important for the auditory sensory epithelium, where deviations from the normal spatial and temporal pattern of auditory progenitor cell (prosensory cell) proliferation and differentiation result in abnormal cellular organization and, thus, auditory dysfunction. The molecular mechanisms involved in the timing and coordination of auditory prosensory proliferation and differentiation are poorly understood. Here we identify the RNAbinding protein LIN28B as a critical regulator of developmental timing in the murine cochlea. We show that Lin28b and its opposing let-7 miRNAs are differentially expressed in the auditory sensory lineage, with Lin28b being highly expressed in undifferentiated prosensory cells and let-7 miRNAs being highly expressed in their progeny-hair cells (HCs) and supporting cells (SCs). Using recently developed transgenic mouse models for LIN28B and let-7g, we demonstrate that prolonged LIN28B expression delays prosensory cell cycle withdrawal and differentiation, resulting in HC and SC patterning and maturation defects. Surprisingly, let-7g overexpression, although capable of inducing premature prosensory cell cycle exit, failed to induce premature HC differentiation, suggesting that LIN28B's functional role in the timing of differentiation uses let-7 independent mechanisms. Finally, we demonstrate that overexpression of LIN28B or let-7g can significantly alter the postnatal production of HCs in response to Notch inhibition; LIN28B has a positive effect on HC production, whereas let-7 antagonizes this process. Together, these results implicate a key role for the LIN28B/let-7 axis in regulating postnatal SC plasticity.Lin28b | Let-7 | hair cell | cochlea | regeneration

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Section: Lin28b Overexpression Results In a Delay In Prosensory Cell mentioning

confidence: 98%

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

Golden

Benito-Gonzalez

Doetzlhofer

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The diminished proliferation that occurs in p27 knockout mice as they age between two weeks and two months may reflect a drop in the expression of cyclins or cyclin dependent kinases. Cyclin D1 has been shown to be dynamically expressed in supporting cells and hair cells in the early postnatal (P0) organ of Corti and tapering off by P15, with no observed expression in the adult [31]. This observation has led to speculation that over expression of Cyclin D1 in the adult organ of Corti may be advantageous in driving supporting cell proliferation as a means to stimulate hair cell regeneration.…”

Section: Discussionmentioning

confidence: 99%

The Cyclin Dependent Kinase Inhibitor p27Kip1 Maintains Terminal Differentiation in the Mouse Organ of Corti

Kil¹

2011

TOOTORJ

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Abstract:Background: In mammals, sensory hair cells and supporting cells that comprise the auditory epithelium (i.e. organ of Corti) lose the ability to proliferate or regenerate after embryogenesis and are considered terminally differentiated. Previously, it was demonstrated that deletion of p27Kip1 , a cyclin dependent kinase inhibitor, extends the period of cellular proliferation beyond embryogenesis in the organ of Corti, resulting in supernumary supporting cells and hair cells. Methodology/Principle Findings:We now report that p27 deletion results in an increased number of inner and outer hair cells at one month of age. These hair cells display normal phenotypes including uptake of AM1-43, a mechanotransduction dye. Outer Hair Cells (OHCs) in the p27-/-cochlea appropriately express Prestin, the cellular protein essential for OHC electromotility. This has not been observed in new hair cells induced by deletion of Rb or over expression of Atoh1.Ototoxic antibiotics (aminoglycosides) can cause hair cell loss resulting in hearing loss. In p27Kip1 +/-and -/-mice, aminoglycosides induce de novo supporting cell proliferation and hair cell regeneration. Thus, in addition to mediating cell cycle withdrawal during embryogenesis, p27 blocks cycle re-entry after embryogenesis and maintains the terminally differentiated state in the organ of Corti. In p27Kip1 +/-and -/-mice, Cyclin E expression was observed in supporting cells on postnatal day 0, increased in expression by postnatal day 7 and was maintained into adulthood. Following p27 inhibition, Cyclin E expression in supporting cells is presumed to drive cell cycle re-entry. Conclusions/Significance:We propose that CyclinE is the dominant cyclin in the supporting cells and release from p27 inhibition allows supporting cell to proliferation and hair cell regeneration.

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“…In support with this conclusion, as described in Chapter 2, deletion of p27 in neonatal PCs caused proliferation of both IPCs and OPCs. Because p27 Kip1 expression is maintained in adult SCs, 65,94 we then determined whether acute ablation of p27 in adult (P30) PCs would also lead to a similar phenotype as Sox2 ablation in adult SCs. Because Prox1 becomes undetectable at adult ages, 83 …”

Section: Sox2 Deletion In Adult Inner Pillar Cells Leads To Limited Pmentioning

confidence: 99%

“…This finding is somewhat surprising in that p27 is not necessary to keep DCs quiescent because p27 is the only cell cycle inhibitor reported in postnatal DCs. 94 However it is possible that DCs lack key positive cell cycle regulators, and thus do not need p27 to maintain quiescence. Consistently, cyclin D1 controls the proliferative capacity of HCs in p19 -/-; p21 -/-double knockout mice, 94 and only those HCs with cyclin D1 expression proliferate.…”

Section: Heterogeneous Signals Of Cell Cycle Regulation In Different mentioning

confidence: 99%

“…94 However it is possible that DCs lack key positive cell cycle regulators, and thus do not need p27 to maintain quiescence. Consistently, cyclin D1 controls the proliferative capacity of HCs in p19 -/-; p21 -/-double knockout mice, 94 and only those HCs with cyclin D1 expression proliferate. Because postnatal DCs have undetectable or very low levels of cyclin D1, 94 it might account for why p27-negative DCs do not proliferate.…”

Section: Heterogeneous Signals Of Cell Cycle Regulation In Different mentioning

confidence: 99%

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Characterization of the Key Mouse Cochlear Developmental Genes for Auditory Hair Cell Regeneration

Liu¹

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Cell cycle regulation in the inner ear sensory epithelia: Role of cyclin D1 and cyclin-dependent kinase inhibitors

Cited by 66 publications

References 40 publications

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

The Cyclin Dependent Kinase Inhibitor p27Kip1 Maintains Terminal Differentiation in the Mouse Organ of Corti

Characterization of the Key Mouse Cochlear Developmental Genes for Auditory Hair Cell Regeneration

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