Gene disruption of p27
            <sup>Kip1</sup>
            allows cell proliferation in the postnatal and adult organ of Corti

Löwenheim, Hubert; Furness, David N.; Kil, Jonathan; Zinn, Christoph; Gültig, Karina; Fero, Matthew L.; Frost, Deanna; Gummer, Anthony W.; Roberts, James M.; Rubel, Edwin W.; Hackney, Carole M.; Zenner, Hans‐Peter

doi:10.1073/pnas.96.7.4084

Cited by 340 publications

(283 citation statements)

References 29 publications

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“…2; Chen et al, 2002;Kiernan et al, 2005a;Wang et al, 2005). We and others previously have shown that the longer and thinner mature organ of Corti is derived from a shorter and thicker postmitotic precursor domain (Ruben, 1967;Chen and Segil, 1999;Lowenheim et al, 1999), likely through cellular intercalation movements characteristic of convergent extension (Chen et al, 2002;McKenzie et al, 2004;Wang et al, 2005). Such a morphogenesis process would predict that the precursors for hair cells and supporting cells line up in columns of cells spanning the depth of the epithelium in the primordial organ of Corti and that cellular intercalation during terminal differentiation leads to the spreading of the cells in the longitudinal direction and the formation of a single layer of hair cells (Chen et al, 2002;Wang et al, 2005).…”

Section: Morphogenesis Of the Inner Ear Sensory Lineage Marked By Thementioning

confidence: 96%

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

et al. 2006

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The basic helix-loop-helix (bHLH) gene Hes6 is known to promote neural differentiation in vitro. Here, we report the expression and functional studies of Hes6 in the inner ear. The expression of Hes6 appears to be parallel to that of Math1 (also known as Atoh1), a bHLH gene necessary and sufficient for hair cell differentiation. Hes6 is expressed initially in the presumptive hair cell precursors in the cochlea. Subsequently, the expression of Hes6 is restricted to morphologically differentiated hair cells. Similarly, the expression of Hes6 in the vestibule is in the hair cell lineage. Hes6 is dispensable for hair cell differentiation, and its expression in inner ear hair cells is abolished in the Math1-null animals. Furthermore, the introduction of Hes6 into the cochlea in vitro is not sufficient to promote sensory or neuronal differentiation. Therefore, Hes6 is downstream of Math1 and its expression in the inner ear delineates the sensory lineage. However, the role of Hes6 in the inner ear remains elusive.

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Section: Morphogenesis Of the Inner Ear Sensory Lineage Marked By Thementioning

confidence: 96%

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

et al. 2006

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“…Deletion of the cyclin-dependent kinase inhibitor, p27 Kip1 , in mice leads to production of supernumerary cells in the organ of Corti through excessive mitoses that extend significantly past the normal developmental period (Chen and Segil 1999;Löwenheim et al 1999). Two other cell cycle regulatory genes, p19 Ink4d and retinoblastoma, are also necessary for normal developmental cell cycle exit in the organ of Corti (Chen et al 2003;Sage et al 2005;Mantela et al 2005).…”

Section: Are Inner Ear Support Cells Stem-like Cells?mentioning

confidence: 99%

“…Non-sensory SCs serve as progenitors to regenerated HCs in nonmammalian ears and in the adult mammalian vestibular sensory epithelia (SE; reviewed in Matsui and Cotanche 2004;Matsui et al 2005;Oesterle and Stone 2008). Under certain experimental circumstances, SCs in neonatal organ of Corti can give rise to new HCs via mitotic pathways (Chen and Segil 1999;Löwenheim et al 1999;Mantela et al 2005;Sage et al 2005;White et al 2006) or by the non-mitotic conversion of SCs into HCs upon altering Notch signaling with N-S-phenyl-glycine-t-butyl ester (DAPT: an inhibitor of gamma secretase: Woods et al 2004;Yamamoto et al 2006). SCs can be converted into HCs upon transfection of the developmental gene Atoh1 (Math1, Zheng and Gao 2000;Shou et al 2003;Woods et al 2004;Izumikawa et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Oesterle

Campbell

Taylor³

et al. 2007

JARO

218

245

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Inner ear hair cells detect environmental signals associated with hearing, balance, and body orientation. In humans and other mammals, significant hair cell loss leads to irreversible hearing and balance deficits, whereas hair cell loss in nonmammalian vertebrates is repaired by the spontaneous generation of replacement hair cells. Research in mammalian hair cell regeneration is hampered by the lack of in vivo damage models for the adult mouse inner ear and the paucity of cell-type-specific markers for nonsensory cells within the sensory receptor epithelia. The present study delineates a protocol to drug damage the adult mouse auditory epithelium (organ of Corti) in situ and uses this protocol to investigate Sox2 and Jagged1 expression in damaged inner ear sensory epithelia. In other tissues, the transcription factor Sox2 and a ligand member of the Notch signaling pathway, Jagged1, are involved in regenerative processes. Both are involved in early inner ear development and are expressed in developing support cells, but little is known about their expressions in the adult. We describe a nonsurgical technique for inducing hair cell damage in adult mouse organ of Corti by a single high-dose injection of the aminoglycoside kanamycin followed by a single injection of the loop diuretic furosemide. This drug combination causes the rapid death of outer hair cells throughout the cochlea. Using immunocytochemical techniques, Sox2 is shown to be expressed specifically in support cells in normal adult mouse inner ear and is not affected by drug damage. Sox2 is absent from auditory hair cells, but is expressed in a subset of vestibular hair cells. Double-labeling experiments with Sox2 and calbindin suggest Sox2-positive hair cells are Type II. Jagged1 is also expressed in support cells in the adult ear and is not affected by drug damage. Sox2 and Jagged1 may be involved in the maintenance of support cells in adult mouse inner ear.

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“…For instance, manipulating levels of retinoic acid in cultured developing cochleae and knocking out the p27 Kip1 gene have been shown to lead to overproduction of hair cells. [1][2][3] The former example deals with a secreted (diffusible) gene product and can be done in the mature cochlea. The latter example, p27 Kip1 knock out, can presently be accomplished only at the germline intervention level.…”

Section: Introductionmentioning

confidence: 99%

Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer

2000

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Cochlear gene transfer is a promising new approach for inner ear therapy. Previous studies have demonstrated hair cell protection with cochlear gene transfer not only in the inoculated, but also in the uninoculated ear. To characterize the kinetics of viral spread, we investigated the extent of transgene expression in the contralateral (uninoculated) cochlea after unilateral adenoviral cochlear gene transfer. We used a lacZ reporter gene vector, and demonstrated spread of the adenovirus into the cerebrospinal fluid (CSF) after cochlear inoculation of 25 l viral vector. Direct virus application into the CSF resulted in transduction of both

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Gene disruption of p27 ^Kip1 allows cell proliferation in the postnatal and adult organ of Corti

Abstract: Hearing loss is most often the result of hair-cell degeneration due to genetic abnormalities or ototoxic and traumatic insults. In the postembryonic and adult mammalian auditory sensory epithelium, the organ of Corti, no hair-cell regeneration has ever been observed. However

Cited by 340 publications

References 29 publications

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer

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Gene disruption of p27 Kip1 allows cell proliferation in the postnatal and adult organ of Corti

Abstract: Hearing loss is most often the result of hair-cell degeneration due to genetic abnormalities or ototoxic and traumatic insults. In the postembryonic and adult mammalian auditory sensory epithelium, the organ of Corti, no hair-cell regeneration has ever been observed. However

Cited by 340 publications

References 29 publications

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer

Contact Info

Product

Resources

About

Gene disruption of p27 ^Kip1 allows cell proliferation in the postnatal and adult organ of Corti