Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial cochlea.

IF 3.7 2区 生物学 Q1 DEVELOPMENTAL BIOLOGY Development Pub Date : 2024-11-01 Epub Date: 2024-11-05 DOI:10.1242/dev.202949
Sandra de Haan, Agustin A Corbat, Christopher R Cederroth, Lisa G Autrum, Simona Hankeova, Elizabeth C Driver, Barbara Canlon, Matthew W Kelley, Emma R Andersson
{"title":"Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial cochlea.","authors":"Sandra de Haan, Agustin A Corbat, Christopher R Cederroth, Lisa G Autrum, Simona Hankeova, Elizabeth C Driver, Barbara Canlon, Matthew W Kelley, Emma R Andersson","doi":"10.1242/dev.202949","DOIUrl":null,"url":null,"abstract":"<p><p>Notch signaling patterns the cochlear organ of Corti, and individuals with the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus experience hearing loss. We investigated the function of Jag1 in cochlear patterning and signaling using Jag1Ndr/Ndr mice, which are a model of Alagille syndrome. Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types further revealed that Jag1 represses Notch activation in lateral supporting cells and demonstrated a function for Jag1 in gene regulation and development of outer hair cells. Surprisingly, ectopic 'outer hair cell-like' cells were present in the medial compartment and pillar cell region of Jag1Ndr/Ndr cochleae, yet they exhibited location-dependent expression of the inner hair cell fate-determinant Tbx2, suggesting Jag1 is required for Tbx2 to drive inner hair cell commitment. This study thus identifies new roles for Jag1 in supporting cells, and in outer hair cell specification and positioning.</p>","PeriodicalId":11375,"journal":{"name":"Development","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Development","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1242/dev.202949","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Notch signaling patterns the cochlear organ of Corti, and individuals with the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus experience hearing loss. We investigated the function of Jag1 in cochlear patterning and signaling using Jag1Ndr/Ndr mice, which are a model of Alagille syndrome. Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types further revealed that Jag1 represses Notch activation in lateral supporting cells and demonstrated a function for Jag1 in gene regulation and development of outer hair cells. Surprisingly, ectopic 'outer hair cell-like' cells were present in the medial compartment and pillar cell region of Jag1Ndr/Ndr cochleae, yet they exhibited location-dependent expression of the inner hair cell fate-determinant Tbx2, suggesting Jag1 is required for Tbx2 to drive inner hair cell commitment. This study thus identifies new roles for Jag1 in supporting cells, and in outer hair cell specification and positioning.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Jag1 可抑制外侧支持细胞的 Notch 激活,并抑制内侧耳蜗外毛细胞的命运。
诺奇(Notch)信号对耳蜗科蒂器官(cochlear organ of Corti)进行模式化,因此患有与 JAG1/NOTCH2 相关的遗传疾病阿拉吉尔综合征(Alagille Syndrome)的患者会出现听力损失。我们利用阿拉吉尔综合征模型 Jag1Ndr/Ndr 小鼠研究了 Jag1 在耳蜗模式化和信号传导中的功能。Jag1Ndr/Ndr 小鼠表现出预期的前庭和听觉障碍,异位内毛细胞呈剂量依赖性增加,外毛细胞减少。Corti器官的单细胞RNA测序表明,与内耳发育和耳聋相关的基因出现了全面失调。对单个细胞类型的分析进一步显示,Jag1抑制了侧支持细胞中Notch的激活,并证明了Jag1在基因调控和外毛细胞发育中的功能。令人惊讶的是,Jag1Ndr/Ndr耳蜗的内侧区和支柱细胞区存在异位的 "外毛细胞样 "细胞,但它们表现出了内毛细胞命运决定因子Tbx2的位置依赖性表达,这表明Jag1是Tbx2驱动内毛细胞承诺所必需的。因此,这项研究确定了 Jag1 在支持细胞以及外毛细胞规格化和定位中的新作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Development
Development 生物-发育生物学
CiteScore
6.70
自引率
4.30%
发文量
433
审稿时长
3 months
期刊介绍: Development’s scope covers all aspects of plant and animal development, including stem cell biology and regeneration. The single most important criterion for acceptance in Development is scientific excellence. Research papers (articles and reports) should therefore pose and test a significant hypothesis or address a significant question, and should provide novel perspectives that advance our understanding of development. We also encourage submission of papers that use computational methods or mathematical models to obtain significant new insights into developmental biology topics. Manuscripts that are descriptive in nature will be considered only when they lay important groundwork for a field and/or provide novel resources for understanding developmental processes of broad interest to the community. Development includes a Techniques and Resources section for the publication of new methods, datasets, and other types of resources. Papers describing new techniques should include a proof-of-principle demonstration that the technique is valuable to the developmental biology community; they need not include in-depth follow-up analysis. The technique must be described in sufficient detail to be easily replicated by other investigators. Development will also consider protocol-type papers of exceptional interest to the community. We welcome submission of Resource papers, for example those reporting new databases, systems-level datasets, or genetic resources of major value to the developmental biology community. For all papers, the data or resource described must be made available to the community with minimal restrictions upon publication. To aid navigability, Development has dedicated sections of the journal to stem cells & regeneration and to human development. The criteria for acceptance into these sections is identical to those outlined above. Authors and editors are encouraged to nominate appropriate manuscripts for inclusion in one of these sections.
期刊最新文献
Differential vegfc expression dictates lymphatic response during zebrafish heart development and regeneration. Establishment of CRISPR/Cas9-based knock-in in a hemimetabolous insect: targeted gene tagging in the cricket Gryllus bimaculatus. The unique functions of Runx1 in skeletal muscle maintenance and regeneration are facilitated by an ETS interaction domain. Contributions of the Dachsous intracellular domain to Dachsous-Fat signaling. Lgr5+ intestinal stem cells are required for organoid survival after genotoxic injury.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1