Spatiotemporally controlled overexpression of Cyclin D1 triggers generation of supernumerary cells in the postnatal mouse inner ear
| Autor: | Shikha Tarang, Kay Uwe Wagner, Michael D. Weston, Umesh Pyakurel, Sonia M. Rocha-Sanchez, Timothy A. Jones, Sarath Vijayakumar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Time Factors Otoacoustic Emissions Spontaneous Mitosis Mice Transgenic Biology Retinoblastoma Protein Article 03 medical and health sciences 0302 clinical medicine Cyclin D1 medicine otorhinolaryngologic diseases Basic Helix-Loop-Helix Transcription Factors Evoked Potentials Auditory Brain Stem Animals Inner ear Phosphorylation Cochlea Cell Proliferation Vestibular system Hair Cells Auditory Inner Cell cycle Embryonic stem cell Vestibular Evoked Myogenic Potentials Sensory Systems Cell biology Up-Regulation 030104 developmental biology medicine.anatomical_structure Organ of Corti Ear Inner Myosin VIIa Female sense organs 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Hear Res |
| Popis: | The retinoblastoma family of pocket proteins (pRBs), composed of Rb1, p107, and p130 are negative regulators of cell-cycle progression. The deletion of any individual pRB in the auditory system triggers hair cells' (HCs) and supporting cells' (SCs) proliferation to different extents. Nevertheless, accessing their combined role in the inner ear through conditional or complete knockout methods is limited by the early mortality of the triple knockout. In quiescent cells, hyperphosphorylation and inactivation of the pRBs are maintained through the activity of the Cyclin-D1-cdk4/6 complex. Cyclin D1 (CycD1) is expressed in the embryonic and neonatal inner ear. In the mature organ of Corti (OC), CycD1 expression is significantly downregulated, paralleling the OC mitotic quiescence. Earlier studies showed that CycD1 overexpression leads to cell-cycle reactivation in cultures of inner ear explants. Here, we characterize a Cre-activated, Doxycycline (Dox)-controlled, conditional CycD1 overexpression model, which when bred to a tetracycline-controlled transcriptional activator and the Atoh1-cre mouse lines, allow for transient CycD1 overexpression and pRBs' downregulation in the inner ear in a reversible fashion. Analyses of postnatal mice's inner ears at various time points revealed the presence of supernumerary cells throughout the length of the cochlea and in the vestibular end-organs. Notably, most supernumerary cells were observed in the inner hair cells' (IHCs) region, expressed myosin VIIa (M7a), and showed no signs of apoptosis at any of the time points analyzed. Auditory and vestibular phenotypes were similar between the different genotypes and treatment groups. The fact that no significant differences were observed in auditory and vestibular function supports the notion that the supernumerary cells detected in the adult mice cochlea and macular end-organs may not impair auditory functions. |
| Databáze: | OpenAIRE |
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