Glass和Pointed的协同激活促进果蝇眼盘中的神经元身份-动脉网

Synergistic activation by Glass and Pointed promotes neuronal identity in the Drosophila eye disc

Nature 等信源发布 2024-08-17 03:01

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AbstractThe integration of extrinsic signaling with cell-intrinsic transcription factors can direct progenitor cells to differentiate into distinct cell fates. In the developing Drosophila eye, differentiation of photoreceptors R1–R7 requires EGFR signaling mediated by the transcription factor Pointed, and our single-cell RNA-Seq analysis shows that the same photoreceptors require the eye-specific transcription factor Glass.

摘要外在信号与细胞内在转录因子的整合可以指导祖细胞分化为不同的细胞命运。在发育中的果蝇眼中，光感受器R1-R7的分化需要由转录因子介导的EGFR信号传导，我们的单细胞RNA-Seq分析表明，相同的光感受器需要眼睛特异性转录因子玻璃。

We find that ectopic expression of Glass and activation of EGFR signaling synergistically induce neuronal gene expression in the wing disc in a Pointed-dependent manner. Targeted DamID reveals that Glass and Pointed share many binding sites in the genome of developing photoreceptors. Comparison with transcriptomic data shows that Pointed and Glass induce photoreceptor differentiation through intermediate transcription factors, including the redundant homologs Scratch and Scrape, as well as directly activating neuronal effector genes.

我们发现玻璃的异位表达和EGFR信号的激活以一种指向依赖的方式协同诱导翼盘中的神经元基因表达。靶向DamID揭示了玻璃和尖头在发育中的光感受器的基因组中共享许多结合位点。与转录组学数据的比较表明，尖头和玻璃通过中间转录因子诱导光感受器分化，包括冗余同源物刮擦和刮伤，以及直接激活神经元效应基因。

Our data reveal synergistic activation of a multi-layered transcriptional network as the mechanism by which EGFR signaling induces neuronal identity in Glass-expressing cells..

我们的数据揭示了多层转录网络的协同激活，这是EGFR信号在玻璃表达细胞中诱导神经元身份的机制。。

IntroductionHow cell fates are specified is a central question in developmental biology. Although some fates are determined by direct lineage inheritance or stochastic choice, cell–cell signaling is the most common mechanism for assigning cells distinct fates. However, most signaling pathways are used in multiple developmental contexts and induce specific differentiation pathways through interactions with tissue-specific transcription factors1.

。尽管某些命运是由直接谱系遗传或随机选择决定的，但细胞间信号传导是分配细胞不同命运的最常见机制。然而，大多数信号通路用于多种发育背景，并通过与组织特异性转录因子的相互作用诱导特定的分化途径1。

These intrinsic factors may determine cellular identity, while extrinsic signals control the time of onset and spatial location of differentiation. For example, cells are committed to the eosinophil lineage by expression of GATA transcription factors, but eosinophil maturation and expansion require interleukin-5 signaling2.

这些内在因素可能决定细胞身份，而外在信号控制分化的起始时间和空间位置。例如，细胞通过表达GATA转录因子致力于嗜酸性粒细胞谱系，但嗜酸性粒细胞成熟和扩增需要白细胞介素-5信号传导2。

Intrinsic and extrinsic inputs can be integrated at the transcriptional level; in spinal motor neuron differentiation, the retinoic acid receptor recruits the histone acetyltransferase CBP to activate chromatin on target genes of the intrinsic transcription factor Neurogenin 23. Combinatorial regulation of differentiation by intrinsic factors and extrinsic signaling is thought to occur frequently during development, but there are few examples for which the mechanism of transcriptional integration has been studied at a genome-wide scale.Differentiation of Drosophila photoreceptor neurons from eye disc epithelial progenitors is a well-characterized system in which external signals and intrinsic factors are known to play important roles.

内在和外在输入可以在转录水平上整合；在脊髓运动神经元分化中，视黄酸受体募集组蛋白乙酰转移酶CBP以激活内在转录因子Neurogenin 23靶基因上的染色质。内在因素和外在信号传导对分化的组合调控被认为在发育过程中经常发生，但在全基因组范围内研究转录整合机制的例子很少。果蝇感光神经元与眼盘上皮祖细胞的分化是一个特征明确的系统，已知外部信号和内在因素在其中起重要作用。

The first photoreceptor in each cluster to differentiate, R8, is specified by the proneural transcription factor Atonal (Ato)4. Differentiation of the other seven photoreceptors in an invariant sequence is induced by the epidermal growth factor (EGFR) ligand Spitz and other signa.

每个簇中第一个分化的光感受器R8由前神经转录因子Atonal（Ato）4指定。表皮生长因子（EGFR）配体Spitz和其他信号诱导其他七个光感受器以不变序列分化。

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differentially affects photoreceptor subtype differentiation

差异影响光感受器亚型分化

In mutants lacking the zinc finger transcription factor Gl, the number of neurons in each ommatidial cluster is reduced to a variable extent12,13. To understand which photoreceptor subtypes are affected by the loss of gl function, we performed single-cell RNA-Seq (scRNA-Seq) analysis of gl60j null mutant10,11 white prepupal eye discs and compared the results to our previous characterization of wild-type eye discs21.

在缺乏锌指转录因子Gl的突变体中，每个小眼簇中的神经元数量减少到可变的程度12,13。为了了解哪些感光细胞亚型受到gl功能丧失的影响，我们对gl60j无效突变体10,11白色乳头前眼盘进行了单细胞RNA-Seq（scRNA-Seq）分析，并将结果与我们之前对野生型眼盘的表征进行了比较21。

Since the mutant and control datasets were generated at different times, we performed data integration in Seurat to enable a comparative analysis (Fig. 1a). A UMAP plot of the integrated data showed that all of the expected eye cell types were present in the gl mutant, but there was a severe reduction in the numbers of the late-born photoreceptors R1, R6, and R7 and of fully differentiated photoreceptors, and an increase in the proportion of undifferentiated cells assigned to the preproneural (Ppn), morphogenetic furrow (MF) and second mitotic wave (SMW) clusters (Fig. 1b).

由于突变体和对照数据集是在不同的时间生成的，因此我们在Seurat中进行了数据整合，以进行比较分析（图1a）。综合数据的UMAP图显示，gl突变体中存在所有预期的眼细胞类型，但晚期出生的光感受器R1，R6和R7以及完全分化的光感受器的数量严重减少，并且分配给前神经（Ppn），形态发生沟（MF）和第二有丝分裂波（SMW）簇的未分化细胞比例增加（图1b）。

Trajectory inference on the photoreceptor clusters using Monocle 3 showed that in gl mutants, the differentiation trajectories of R1, R6, and R7 were incomplete, missing part of the path that connects them to the differentiated photoreceptor cluster (Fig. 1c, d). The earlier-born photoreceptors showed a more subtle disruption of their trajectories at late differentiation stages (Fig. 1c, d).

使用Monocle 3对光感受器簇进行的轨迹推断表明，在gl突变体中，R1，R6和R7的分化轨迹不完整，缺少将它们连接到分化的光感受器簇的路径的一部分（图1c，d）。早期出生的光感受器在分化后期表现出更微妙的轨迹破坏（图1c，d）。

These data show that gl is important for the differentiation of late-born photoreceptors R1, R6, and R7, and for late photoreceptor differentiation in general.Fig. 1: scRNA-Seq characterization of photoreceptor differentiation defects in gl mutants.a UMAP dimensional plot of scRNA-Seq data from wild-type and gl60j white prepupal eye discs harmonized using the Seurat integration method.

这些数据表明，gl对于晚期感光细胞R1，R6和R7的分化以及一般晚期感光细胞的分化很重要。图1:gl突变体中光感受器分化缺陷的scRNA-Seq表征。使用Seurat整合方法协调来自野生型和gl60j白色prepupal眼盘的scRNA-Seq数据的UMAP维度图。

The same colors.

相同的颜色。

Data availability

数据可用性

All the raw data for scRNA-seq, bulk RNA-Seq, and DamID-Seq have been archived online with Gene Expression Omnibus (GEO) with the accession number GSE256221. Source data are provided with this paper.

scRNA-seq，批量RNA-seq和DamID-seq的所有原始数据均已通过Gene Expression Omnibus（GEO）在线存档，登录号为GSE256221。本文提供了源数据。

Code availability

代码可用性

No custom code was created for this paper. However, we have deposited the code we used to analyze our data in Github71 (https://doi.org/10.5281/zenodo.12770071).

没有为此纸张创建自定义代码。然而，我们已经将用于分析数据的代码存放在Github71中(https://doi.org/10.5281/zenodo.12770071)。

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Wang, H. et al. Synergistic activation by Glass and Pointed promotes neuronal identity in the Drosophila eye disc. Github https://doi.org/10.5281/zenodo.12770071 (2024).Download referencesAcknowledgementsWe thank Ethan Bier, Andrea Brand, Iswar Hariharan, Christian Klämbt, the Bloomington Drosophila Stock Center, the Developmental Studies Hybridoma Bank, and the Vienna Drosophila Resource Center for fly stocks and reagents.

Wang，H。等人。玻璃和尖头的协同激活促进果蝇眼盘中的神经元身份。Githubhttps://doi.org/10.5281/zenodo.12770071（2024年）。下载参考文献致谢我们感谢Ethan Bier，Andrea Brand，Iswar Hariharan，Christian Klämbt，布卢明顿果蝇库存中心，发育研究杂交瘤银行和维也纳果蝇资源中心的果蝇库存和试剂。

The information available on FlyBase was invaluable for this study. We thank Gael Westby, Peter Meyn, and Adriana Heguy in NYU Langone’s Genome Technology Center (RRID: SCR_017929) for coordinating DamID-Seq and RNA-Seq experimental planning, sample submission, processing, and sequencing. We are grateful to Alex Donovan, Anna Malkowska, Paola Angulo Salgado, Markus Schober, Hyung Don Ryoo, Jain Wu, and Maria Bustillo for advice on experimental planning and data processing.

FlyBase上提供的信息对这项研究非常宝贵。我们感谢纽约大学兰贡分校基因组技术中心（RRID:SCR\U 017929）的盖尔·韦斯比（Gael Westby），彼得·梅恩（Peter Meyn）和阿德里亚娜·赫盖（Adriana Heguy）协调DamID-Seq和RNA-Seq实验计划，样品提交，处理和测序。我们感谢Alex Donovan，Anna Malkowska，Paola Angulo Salgado，Markus Schober，Hyung Don Ryoo，Jain Wu和Maria Bustillo就实验计划和数据处理提供的建议。

We thank Sophia He, Ariel Hairston, Dhaval Gandhi, and Genie Jang for technical assistance, and Yan Deng for confocal microscope training and maintenance. The manuscript was improved by the critical comments of Maria Bustillo and Neha Ghosh. This work was supported by NIH grants R21EY024826 and R21EY031442 to J.E.T., a grant from the Retina Research Foundation to G.M., and Swiss National Science Foundation grant 310030_219348 to S.G.S.Author informationAuthor notesCarolyn A.

我们感谢Sophia He，Ariel Hairston，Dhaval Gandhi和Genie Jang的技术援助，以及Yan Deng的共聚焦显微镜培训和维护。Maria Bustillo和Neha Ghosh的批评性评论改进了手稿。这项工作得到了NIH对J.E.T.的R21EY024826和R21EY031442资助，视网膜研究基金会对G.M.的资助，以及瑞士国家科学基金会对S.G.S.作者信息作者notesCarolyn a.的310030\U 219348资助。

MorrisonPresent address: 10x Genomics, Pleasanton, CA, 94588, USAAntonia TerrizzanoPresent address: Biology of Centrosomes and Genetic Instability Team, Curie Institute, PSL Research University, CNRS, UMR144, 12 rue Lhomond, Paris, 75005, FrancePhoenix ChenPresent address: Department of Biology, Boston University, Boston, MA, USAAuthors and AffiliationsDepartment of Cell Biology, NYU Grossman Sc.

莫里森目前的地址：10x Genomics，普莱森顿，加利福尼亚州，94588，USAAntonia TERRIZZANO目前的地址：中心体生物学和遗传不稳定性团队，PSL研究大学居里研究所，CNRS，UMR144，12 rue Lhomond，Paris，75005，FrancePhoenix Chen目前的地址：美国马萨诸塞州波士顿市波士顿大学生物学系作者和附属机构纽约大学格罗斯曼分校细胞生物学系。

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PubMed Google ScholarContributionsInvestigation: H.W., K.K.B.R., K.Y., C.A.M., A.T., P.C., A.J., C.F., J.E.T.; Data analysis: H.W., K.K.B.R., A.K.-J.; Supervision and funding acquisition: S.G.S., G.M., J.E.T.; Writing: original draft: H.W.; Writing: review and editing: K.K.B.R., K.Y., C.A.M., A.T., C.F., S.G.S., J.E.T.; Project management: J.E.T.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献调查：H.W.，K.K.B.R.，K.Y.，C.A.M.，A.T.，P.C.，A.J.，C.F.，J.E.T。；数据分析：H.W.，K.K.B.R.，A.K.-J。；监督和资金获取：S.G.S.，G.M.，J.E.T。；。；写作：评论和编辑：K.K.B.R.，K.Y.，C.A.M.，A.T.，C.F.，S.G.S.，J.E.T。；项目管理：J.E.T.通讯作者。

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杰西卡·E·特雷斯曼。道德宣言

Competing interests

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C.A.M. is a shareholder of 10X Genomics. G.M. is the co-owner of Genetivision Corporation. The other authors declare no competing interests.

C、 A.M.是10X Genomics的股东。G、 M.是Genetivision Corporation的共同所有者。其他作者声明没有利益冲突。

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Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleWang, H., Bollepogu Raja, K.K., Yeung, K. et al. Synergistic activation by Glass and Pointed promotes neuronal identity in the Drosophila eye disc.

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Nat Commun 15, 7091 (2024). https://doi.org/10.1038/s41467-024-51429-zDownload citationReceived: 12 February 2024Accepted: 06 August 2024Published: 17 August 2024DOI: https://doi.org/10.1038/s41467-024-51429-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》157091（2024）。https://doi.org/10.1038/s41467-024-51429-zDownload引文收到日期：2024年2月12日接受日期：2024年8月6日发布日期：2024年8月17日OI：https://doi.org/10.1038/s41467-024-51429-zShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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