Generation and characterization of Atoh1‐Cre knock‐in mouse line

Yang, Hua; Xie, Xiaoling; Deng, Min; Chen, Xiaowei; Gan, Lin

doi:10.1002/dvg.20648

Cited by 16 publications

(30 citation statements)

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“…However, our loss-of-function data suggest that Hey1 and Hey2 are dispensable for prosensory domain specification but are critical components of the molecular machinery that negatively controls the graded upregulation of Atoh1 in HC precursors during cochlear differentiation. In the murine cochlea, Atoh1 promoter activity can be detected in prosensory cells as early as E12.5 (Woods et al, 2004;Yang et al, 2010;Driver et al, 2013). In contrast, Atoh1 transcript and protein levels are exceedingly low at this stage.…”

Section: Discussionmentioning

confidence: 99%

Hey1 and Hey2 Control the Spatial and Temporal Pattern of Mammalian Auditory Hair Cell Differentiation Downstream of Hedgehog Signaling

Benito-Gonzalez

Doetzlhofer

2014

Journal of Neuroscience

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Mechano-sensory hair cells (HCs), housed in the inner ear cochlea, are critical for the perception of sound. In the mammalian cochlea, differentiation of HCs occurs in a striking basal-to-apical and medial-to-lateral gradient, which is thought to ensure correct patterning and proper function of the auditory sensory epithelium. Recent studies have revealed that Hedgehog signaling opposes HC differentiation and is critical for the establishment of the graded pattern of auditory HC differentiation. However, how Hedgehog signaling interferes with HC differentiation is unknown. Here, we provide evidence that in the murine cochlea, Hey1 and Hey2 control the spatiotemporal pattern of HC differentiation downstream of Hedgehog signaling. It has been recently shown that HEY1 and HEY2, two highly redundant HES-related transcriptional repressors, are highly expressed in supporting cell (SC) and HC progenitors (prosensory cells), but their prosensory function remained untested. Using a conditional double knock-out strategy, we demonstrate that prosensory cells form and proliferate properly in the absence of Hey1 and Hey2 but differentiate prematurely because of precocious upregulation of the pro-HC factor Atoh1. Moreover, we demonstrate that prosensory-specific expression of Hey1 and Hey2 and its subsequent graded downregulation is controlled by Hedgehog signaling in a largely FGFR-dependent manner. In summary, our study reveals a critical role for Hey1 and Hey2 in prosensory cell maintenance and identifies Hedgehog signaling as a novel upstream regulator of their prosensory function in the mammalian cochlea. The regulatory mechanism described here might be a broadly applied mechanism for controlling progenitor behavior in the central and peripheral nervous system.

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Section: Discussionmentioning

confidence: 99%

Hey1 and Hey2 Control the Spatial and Temporal Pattern of Mammalian Auditory Hair Cell Differentiation Downstream of Hedgehog Signaling

Benito-Gonzalez

Doetzlhofer

2014

Journal of Neuroscience

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“…Cre in developing hair cells and a subset of supporting cells starting at ~E14.5 (Yang et al, 2010 Fig. 2A,E; average bundle deviation of 8.6±0.7°).…”

Section: Lis1 Is Localized To the Pericentriolar Region In Developingmentioning

confidence: 99%

Lis1 mediates planar polarity of auditory hair cells through regulation of microtubule organization

et al. 2013

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SUMMARYThe V-shaped hair bundles atop auditory hair cells and their uniform orientation are manifestations of epithelial planar cell polarity (PCP) required for proper perception of sound. PCP is regulated at the tissue level by a conserved core Wnt/PCP pathway. However, the hair cell-intrinsic polarity machinery is poorly understood. Recent findings implicate hair cell microtubules in planar polarization of hair cells. To elucidate the microtubule-mediated polarity pathway, we analyzed Lis1 function in the auditory sensory epithelium in the mouse. We show that conditional deletion of Lis1 in developing hair cells causes defects in cytoplasmic dynein and microtubule organization, resulting in planar polarity defects without overt effects on the core PCP pathway. Lis1 ablation during embryonic development results in defects in hair bundle morphology and orientation, cellular organization and junctional nectin localization. We present evidence that Lis1 regulates localized Rac-PAK signaling in embryonic hair cells, probably through microtubule-associated Tiam1, a guanine nucleotide exchange factor for Rac. Lis1 ablation in postnatal hair cells significantly disrupts centrosome anchoring and the normal V-shape of hair bundles, accompanied by defects in the pericentriolar matrix and microtubule organization. Lis1 is also required for proper positioning of the Golgi complex and mitochondria as well as for hair cell survival. Together, our results demonstrate that Lis1 mediates the planar polarity of hair cells through regulation of microtubule organization downstream of the tissue polarity pathway.

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“…In agreement with this, some adult or fully mature mouse utricle HCs have been shown to still maintain the expression of Sox2 (Hume et al, 2007). Lineage tracing studies show that Atoh1expressing cells can develop into HCs and SCs, whereas Gfi1 expressing cells exclusively differentiate into HCs in the cochlea (Matei et al, 2005;Yang et al, 2010a;Yang et al, 2010b). Therefore, in our opinion, HC fate commitment occurs first at ~E15.5 at the middle-basal turns when Gfi1 expression starts, and this wave further migrates to the basal and apical turns, after which other HC markers such as Myosin VI or Myosin VIIa are turned on.…”

Section: Implications On Mammalian Hair Cell Regenerationmentioning

confidence: 55%

In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation

Owen

Fang

et al. 2012

Developmental Dynamics

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Notch signaling is active in mouse cochlear prosensory progenitors but declines in differentiating sensory hair cells (HCs) mice showed that nearly all HCs experiencing Prox1 expression were OHCs. Surprisingly, these HCs still matured normally with expression of prestin, wild-type-like morphology and uptake of FM4-64FX dye at adult ages. Our results suggest that the developmental program of cochlear differentiating HCs is refractory to Notch reactivation and that Notch is an upstream regulator of Sox2 and Prox1 in cochlear development. In addition, our results support that Sox2 and Prox1 should not be the main blockers for terminal differentiation of HCs newly regenerated from postnatal cochlear SCs that still maintain Sox2 and Prox1 expression.

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Generation and characterization of Atoh1‐Cre knock‐in mouse line

Cited by 16 publications

References 0 publications

Hey1 and Hey2 Control the Spatial and Temporal Pattern of Mammalian Auditory Hair Cell Differentiation Downstream of Hedgehog Signaling

Hey1 and Hey2 Control the Spatial and Temporal Pattern of Mammalian Auditory Hair Cell Differentiation Downstream of Hedgehog Signaling

Lis1 mediates planar polarity of auditory hair cells through regulation of microtubule organization

In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation

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