Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development

Li, Shuangding; Mark, Sharayne; Radde-Gallwitz, Kristen; Schlisner, Rebecca; Chin, Michael T.; Chen, Ping Helen

doi:10.1186/1471-213x-8-20

Cited by 60 publications

(75 citation statements)

References 40 publications

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“…However, a comparison of the effects of HES5 and HEY2 on the repression of Atoh1 revealed differences in strength of inhibition and binding (Fig. S2), suggesting the possibility that different members of the Hes/Hey families could play independent roles in Atoh1 regulation, as previously shown (Zine et al, 2001;Li et al, 2008;Doetzlhofer et al, 2009). While Hes/Hey repressor sequences are present in regulatory elements of atonal homologs separated by hundreds of millions of years of evolution, there are fewer recognizable Hes/Hey motifs associated with proneural genes in non-vertebrate lineages, just as there are fewer homologs of Hes/Hey genes (Rebeiz et al, 2005), suggesting that duplication of the binding sites in the Atoh1 promoter might have paralleled the expansion of the Hes/Hey family of genes, leading to specialization rather than redundancy in mammals.…”

Section: Discussionmentioning

confidence: 77%

“…HEY2, which is also expressed in the organ of Corti with other Hes/Hey family members (Li et al, 2008;Doetzlhofer et al, 2009), was tested using the same reporter constructs co-transfected into HEK 293 cells. Similar to HES5, HEY2 represses expression in an Atoh1 promoter-dependent manner, although site usage varied from that seen with HES5 (Fig.…”

Section: Derepression Of Atoh1 Is Sufficient To Induce Atoh1 Transcrimentioning

confidence: 99%

“…Previous reports suggest that repression is accomplished by the recruitment of co-repressors, such as those encoded by Groucho-related genes (Grg1-4; also known as Tle1-4) in the case of the Hes family, which in turn are able to recruit histone deacetylases (HDACs) to mediate gene inactivation (Fisher et al, 1996;Grbavec and Stifani, 1996;Winkler et al, 2010). In the organ of Corti, Hes/Hey genes are expressed in a complex combinatorial pattern (Doetzlhofer et al, 2009;Tateya et al, 2011) and are needed to maintain supporting cell fate (Zine et al, 2001;Zine and de Ribaupierre, 2002;Hayashi et al, 2008;Li et al, 2008), but the molecular mechanism by which this is accomplished has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter

2016

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Determination of cell fate within the prosensory domain of the developing cochlear duct relies on the temporal and spatial regulation of the bHLH transcription factor Atoh1. Auditory hair cells and supporting cells arise in a wave of differentiation that patterns them into discrete rows mediated by Notch-dependent lateral inhibition. However, the mechanism responsible for selecting sensory cells from within the prosensory competence domain remains poorly understood. We show in mice that rather than being upregulated in rows of cells, Atoh1 is subject to transcriptional activation in groups of prosensory cells, and that highly conserved sites for Hes/Hey repressor binding in the Atoh1 promoter are needed to select the hair cell and supporting cell fate. During perinatal supporting cell transdifferentiation, which is a model of hair cell regeneration, we show that derepression is sufficient to induce Atoh1 expression, suggesting a mechanism for priming the 3′ Atoh1 autoregulatory enhancer needed for hair cell expression.

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Section: Discussionmentioning

confidence: 77%

Section: Derepression Of Atoh1 Is Sufficient To Induce Atoh1 Transcrimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter

2016

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“…Although fate mapping is primarily performed using the Cre/loxP system, we were already using this system to kill HCs and thus needed another mouse genetic tool to trace SCs (Stern and Fraser, 2001). Since Hes5 is expressed in SCs of the postnatal cochlea (Hartman et al, 2009;Lanford et al, 2000;Li et al, 2008;Zine et al, 2001), we characterized a recently generated Hes5-nlsLacZ knock-in allele (Imayoshi et al, 2010). lacZ was strongly expressed throughout the P1 cochlea (Fig.…”

Section: Supporting Cells Acquire a Hair Cell Fatementioning

confidence: 99%

Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo

et al. 2014

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There was an error published in Development 141, 816-829. Edwin W. Rubel was omitted from the authorship of the paper. The correct author list and affiliations appears above.In addition the Acknowledgements and Author contributions sections should read as follows. AcknowledgementsWe thank L. Tong and R. Palmiter (University of Washington) for Pou4f3DTR/+ mice and discussion; S. Baker (St. Jude) for Atoh1-CreERTM mice and discussion; R. Kageyama (Kyoto University) for Hes5-nlsLacZ mice; P. Chambon (Institut Genetique Biologie Moleculaire Cellulaire) for the CreERT2 construct; S. Heller (Stanford University) for the anti-espin antibody and critical reading, J. Corwin, J. Burns and other members of the Corwin laboratory (University of Virginia) as well as members of our laboratories for discussion and critical comments; S. Connell, V. Frohlich, Y. Ouyang and J. Peters (St. Jude) for expertise in confocal imaging; A. Xue, V. Nookala, N. Pham, A. Vu, G. Huang and W. Liu (Stanford University) for excellent technical support; and L. Boykins (University of Memphis), R. Martens and J. Goodwin (University of Alabama) for assistance and expertise in scanning electron microscopy. Author contributionsB.C.C., R.C., E.W.R., A.G.C. and J.Z. developed the concepts or approach; B.C.C., R.C., A.L., Z.L., L.Z., D.-H.N., K.C., K.A.S., J.F., A.G.C. and J.Z. performed experiments or data analysis; B.C.C., R.C., A.G.C. and J.Z. prepared or edited the manuscript prior to submission.The authors apologise to readers for this mistake. DTA/+ alleles allowed selective and inducible hair cell ablation. After hair cell loss was induced at birth, we observed spontaneous regeneration of hair cells. Fate-mapping experiments demonstrated that neighboring supporting cells acquired a hair cell fate, which increased in a basal to apical gradient, averaging over 120 regenerated hair cells per cochlea. The normally mitotically quiescent supporting cells proliferated after hair cell ablation. Concurrent fate mapping and labeling with mitotic tracers showed that regenerated hair cells were derived by both mitotic regeneration and direct transdifferentiation. Over time, regenerated hair cells followed a similar pattern of maturation to normal hair cell development, including the expression of prestin, a terminal differentiation marker of outer hair cells, although many new hair cells eventually died. Hair cell regeneration did not occur when ablation was induced at one week of age. Our findings demonstrate that the neonatal mouse cochlea is capable of spontaneous hair cell regeneration after damage in vivo. Thus, future studies on the neonatal cochlea might shed light on the competence of supporting cells to regenerate hair cells and on the factors that promote the survival of newly regenerated hair cells. 816© 2014. Published by The Company of Biologists Ltd | Development (2014) 141, 816-829 doi

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“…Hes/Hey factors are well-known targets of Notch signaling and are required for inner ear development (Zheng et al, 2000;Zine et al, 2001;Hayashi et al, 2008;Li et al, 2008;Tateya et al, 2011). We asked whether there is a relationship between the expression of the ligands Dl1 and Jag1 and the different Hes/Hey genes.…”

Section: Dl1 and Jag1 Are Associated With Different Notch Targets Durmentioning

confidence: 99%

Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear

et al. 2014

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During inner ear development, Notch exhibits two modes of operation: lateral induction, which is associated with prosensory specification, and lateral inhibition, which is involved in hair cell determination. These mechanisms depend respectively on two different ligands, jagged 1 (Jag1) and delta 1 (Dl1), that rely on a common signaling cascade initiated after Notch activation. In the chicken otocyst, expression of Jag1 and the Notch target Hey1 correlates well with lateral induction, whereas both Jag1 and Dl1 are expressed during lateral inhibition, as are Notch targets Hey1 and Hes5. Here, we show that Jag1 drives lower levels of Notch activity than Dl1, which results in the differential expression of Hey1 and Hes5. In addition, Jag1 interferes with the ability of Dl1 to elicit high levels of Notch activity. Modeling the sensory epithelium when the two ligands are expressed together shows that ligand regulation, differential signaling strength and ligand competition are crucial to allow the two modes of operation and for establishing the alternate pattern of hair cells and supporting cells. Jag1, while driving lateral induction on its own, facilitates patterning by lateral inhibition in the presence of Dl1. This novel behavior emerges from Jag1 acting as a competitive inhibitor of Dl1 for Notch signaling. Both modeling and experiments show that hair cell patterning is very robust. The model suggests that autoactivation of proneural factor Atoh1, upstream of Dl1, is a fundamental component for robustness. The results stress the importance of the levels of Notch signaling and ligand competition for Notch function.

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Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development

Cited by 60 publications

References 40 publications

Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter

Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter

Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo

Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear

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