Expression of LHX3 and SOX2 during mouse inner ear development

Hume, Clifford R.; Bratt, Debra; Oesterle, Elizabeth C.

doi:10.1016/j.modgep.2007.05.002

Cited by 136 publications

(154 citation statements)

References 51 publications

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“…As reported previously, there is a subset of hair cells throughout the epithelium that also express Sox2 (yellow cells in Fig. 1(E,E′); Hume et al 2007;Oesterle et al 2008). Similar to the staining seen in the utricle, this subset of cells does not appear to be innervated by Calretininpositive calyces and is generally located closer to the apical surface of the sensory epithelium ( Fig.…”

Section: The Cristae Ampullarissupporting

confidence: 75%

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Slowik

Bermingham‐McDonogh

2013

JARO

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Balance disorders caused by hair cell loss in the sensory organs of the vestibular system pose a significant health problem worldwide, particularly in the elderly. Currently, this hair cell loss is permanent as there is no effective treatment. This is in stark contrast to nonmammalian vertebrates who robustly regenerate hair cells after damage. This disparity in regenerative potential highlights the need for further manipulation in order to stimulate more robust hair cell regeneration in mammals. In the utricle, Notch signaling is required for maintaining the striolar support cell phenotype into the second postnatal week. Notch signaling has further been implicated in hair cell regeneration after damage in the mature utricle. Here, we investigate the role of Notch signaling in the mature mammalian cristae in order to characterize the Notch-mediated regenerative potential of these sensory organs. For these studies, we used the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-Lalanyl]-S-phenylglycine t-butyl ester (DAPT), in conjunction with a method we developed to culture cristae in vitro. In postnatal and adult cristae, we found that 5 days of DAPT treatment resulted in a downregulation of the Notch effectors Hes1 and Hes5 and also an increase in the total number of Gfi1 + hair cells. Hes5, as reported by Hes5-GFP, was downregulated specifically in peripheral support cells. Using lineage tracing with proteolipid protein (PLP)/CreER;mTmG mice, we found that these hair cells arose through transdifferentiation of support cells in cristae explanted from mice up to 10 weeks of age. These transdifferentiated cells arose without proliferation and were capable of taking on a hair cell morphology, migrating to the correct cell layer, and assembling what appears to be a stereocilia bundle with a long kinocilium. Overall, these data show that Notch signaling is active in the mature cristae and suggest that it may be important in maintaining the support cell fate in a subset of peripheral support cells.

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Section: The Cristae Ampullarissupporting

confidence: 75%

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Slowik

Bermingham‐McDonogh

2013

JARO

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“…The Sox2 antibody was used routinely at dilutions of 1:500-1:1,000. Specificity of the antibody was verified in an earlier study by blocking with a Sox2-specific peptide and eliminating all labeling (Hume et al 2007). The Sox2 antibody stains a single band of 37-40 kD on Western blot (manufacturer's technical information).…”

Section: Antibodiesmentioning

confidence: 97%

Supporting Cell Characteristics in Long-deafened Aged Mouse Ears

Oesterle

Campbell

2009

JARO

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Significant sensory hair cell loss leads to irreversible hearing and balance deficits in humans and other mammals. Future therapeutic strategies to repair damaged mammalian auditory epithelium may involve inserting stem cells into the damaged epithelium, inducing non-sensory cells remaining in the epithelium to transdifferentiate into replacement hair cells via gene therapy, or applying growth factors. Little is currently known regarding the status and characteristics of the non-sensory cells that remain in the deafened auditory epithelium, yet this information is integral to the development of therapeutic treatments. A single high-dose injection of the aminoglycoside kanamycin coupled with a single injection of the loop diuretic furosemide was used to kill hair cells in adult mice, and the mice were examined 1 year after the drug insult. Outer hair cells are lost throughout the entire length of the cochlea and less than a third of the inner hair cells remain in the apical turn. Over 20% and 55% of apical organ of Corti support cells and spiral ganglion cells are lost, respectively. We examined the expression of several known support cell markers to investigate for possible support cell dedifferentiation in the damaged ears. The support cell markers investigated included the microtubule protein acetylated tubulin, the transcription factor Sox2, and the Notch signaling ligand Jagged1. Non-sensory epithelial cells remaining in the organ of Corti retain acetylated tubulin, Sox2 and Jagged1 expression, even when the epithelium has a monolayer-like appearance. These results suggest a lack of marked SC dedifferentiation in these aged and badly damaged ears.

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“…At P0, expression of Sox2 is restricted to supporting cells and to a group of cells within KO (Fig. 1D) (5).…”

Section: Sox2mentioning

confidence: 99%

Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea

Dabdoub

Puligilla

Jones

et al. 2008

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

311

421

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Sox2 is a high-mobility transcription factor that is one of the earliest markers of developing inner ear prosensory domains. In humans, mutations in SOX2 cause sensorineural hearing loss and a loss of function study in mice showed that Sox2 is required for prosensory formation in the cochlea. However, the specific roles of Sox2 have not been determined. Here we illustrate a dynamic role of Sox2 as an early permissive factor in prosensory domain formation followed by a mutually antagonistic relationship with Atoh1, a bHLH protein necessary for hair cell development. We demonstrate that decreased levels of Sox2 result in precocious hair cell differentiation and an over production of inner hair cells and that these effects are likely mediated through an antagonistic interaction between Sox2 and the bHLH molecule Atoh1. Using gain-and loss-of-function experiments we provide evidence for the molecular pathway responsible for the formation of the cochlear prosensory domain. Sox2 expression is promoted by Notch signaling and Prox1, a homeobox transcription factor, is a downstream target of Sox2. These results demonstrate crucial and diverse roles for Sox2 in the development, specification, and maintenance of sensory cells within the cochlea.development ͉ organ of Corti ͉ inner ear ͉ HMG box ͉ bHLH T he sensory epithelium of the mammalian cochlea (the organ of Corti) develops from a pool of prosensory cells derived from the ventral region of the otocyst. Proper development of the cochlea requires that cochlear progenitor cells transition through states of developmental competence, coordinated cell cycle exit, and cell fate specification and differentiation to generate the distinctly fated cell populations within the highly ordered mosaic of the organ of Corti (1). The signal transduction pathways that coordinate cochlear prosensory specification are only beginning to be identified. Moreover, since these signal transduction pathways are unlikely to be linear cascades, it will also be necessary to determine how different pathways are organized into complex signaling networks that ultimately generate precise and unique responses within individual cochlear prosensory cells.Sox (SRY related HMG box) proteins are a group of transcription factors that regulate diverse developmental processes; for instance, Sox2 is a universal marker of stem cells and is also expressed in neural progenitor cells at different stages of central nervous system development. Sox2, along with Sox1 and Sox3, comprise the SoxB1 group. Members of this group are thought to maintain neural precursor cells in a progenitor state by inhibiting bHLH-mediated neuronal differentiation (2). Reciprocally, bHLH proteins must suppress expression and activity of SoxB1 proteins to induce cellular differentiation. A recent loss-of-function study demonstrated that Sox2 is required for development of sensory epithelia, including the organ of Corti, within the inner ear (3). However, despite its absolute necessity for the formation of inner ear sensory epithelia, the spe...

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Expression of LHX3 and SOX2 during mouse inner ear development

Cited by 136 publications

References 51 publications

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

Supporting Cell Characteristics in Long-deafened Aged Mouse Ears

Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea

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