AbstractmicroRNAs are crucial regulators of brain development, however, miRNA regulatory networks are not sufficiently well characterized. By performing small RNA-seq of the mouse embryonic cortex at E14, E17, and P0 as well as in neural progenitor cells and neurons, here we detected clusters of miRNAs that were co-regulated at distinct developmental stages.

摘要microRNA是大脑发育的关键调节因子，然而，miRNA调控网络尚未得到充分表征。通过在E14，E17和P0以及神经祖细胞和神经元中对小鼠胚胎皮层进行小RNA-seq，我们在这里检测到在不同发育阶段共同调节的miRNA簇。

miRNAs such as miR-92a/b acted as hubs during early, and miR-124 and miR-137 during late neurogenesis. Notably, validated targets of P0 hub miRNAs were enriched for downregulated genes related to stem cell proliferation, negative regulation of neuronal differentiation and RNA splicing, among others, suggesting that miRNAs are particularly important for modulating transcriptional programs of crucial factors that guide the switch to neuronal differentiation.

miRNA如miR-92a/b在早期充当中枢，miR-124和miR-137在晚期神经发生期间充当中枢。值得注意的是，P0-hub miRNA的验证靶标富含与干细胞增殖，神经元分化的负调控和RNA剪接等相关的下调基因，这表明miRNA对于调节指导转换的关键因子的转录程序特别重要。神经元分化。

As most genes contain binding sites for more than one miRNA, we furthermore constructed a co-targeting network where numerous miRNAs shared more targets than expected by chance. Using luciferase reporter assays, we demonstrated that simultaneous binding of miRNA pairs to neurodevelopmentally relevant genes exerted an enhanced transcriptional silencing effect compared to single miRNAs.

由于大多数基因含有一个以上miRNA的结合位点，因此我们进一步构建了一个共靶向网络，其中许多miRNA共享的靶标比偶然预期的要多。使用荧光素酶报告基因测定，我们证明与单个miRNA相比，miRNA对与神经发育相关基因的同时结合发挥了增强的转录沉默作用。

Taken together, we provide a comprehensive resource of miRNA longitudinal expression changes during murine corticogenesis. Furthermore, we highlight several potential mechanisms through which miRNA regulatory networks can shape embryonic brain development..

综上所述，我们提供了小鼠皮质发生过程中miRNA纵向表达变化的综合资源。此外，我们强调了miRNA调控网络可以塑造胚胎大脑发育的几种潜在机制。。

IntroductionMammalian brain development is an extraordinarily complex process where neural progenitor cells proliferate and give rise to all neuronal and glial cell types. Numerous transcriptional, post-transcriptional, and epigenetic mechanisms integrate with each other to control progenitor proliferation and self-renewal, differentiation, and lineage commitment as well as migration in a strictly spatio-temporal manner.

引言哺乳动物的大脑发育是一个非常复杂的过程，其中神经祖细胞增殖并产生所有神经元和神经胶质细胞类型。许多转录，转录后和表观遗传机制相互整合，以严格的时空方式控制祖细胞增殖和自我更新，分化和谱系承诺以及迁移。

One of the key regulators of these processes are microRNAs (miRNAs). In most cases, these small RNAs bind to their target mRNAs’ 3’- untranslated region (3’UTR) to induce mRNA degradation or translational inhibition. In the canonical pathway, miRNA genes are transcribed into a pri-miRNA in the cell nucleus by PolII/III1,2.

这些过程的关键调节因子之一是microRNA（miRNA）。在大多数情况下，这些小RNA与其靶mRNA“3”非翻译区（3'UTR）结合以诱导mRNA降解或翻译抑制。在经典途径中，miRNA基因通过PolII/III1,2在细胞核中转录成pri-miRNA。

In subsequent processing steps, the pri-miRNA is cleaved into a hairpin pre-miRNA by the microprocessor complex Drosha-Dgcr8 and transported to the cytoplasm by Exportin-53,4,5,6. In the cytoplasm, the pre-miRNA is bound and cleaved by a complex containing the RNase Dicer1 to form the mature miRNA duplex7.

在随后的加工步骤中，pri-miRNA被微处理器复合物Drosha-Dgcr8切割成发夹前miRNA，并通过Exportin-53,4,5,6转运至细胞质。在细胞质中，pre-miRNA被含有RNase Dicer1的复合物结合并切割，形成成熟的miRNA双链体7。

From this duplex, the functional strand is loaded into the RISC complex, guiding it to the 3′UTR’s target site8. Mice carrying conditional Dicer gene deletions in the embryonic telencephalon have shown a variety of phenotypes in the cerebral cortex, such as reduced cell proliferation and impaired neuronal differentiation, increased apoptosis, defective cortical layering and microcephaly9,10,11,12,13,14.In the brain, 70% of all miRNAs are expressed, most of them in a highly cell-type- and developmental-time-specific manner15.

从这个双链体中，功能链被加载到RISC复合体中，将其引导到3'UTR的目标位点8。。

Given that the total number of human miRNAs is estimated to be ∼2300, at least 1600 different miRNAs may be expressed in the brain16. While this suggests that miRNA regulation is generally important for brain de.

鉴于人类miRNA的总数估计约为2300，至少1600种不同的miRNA可能在大脑中表达16。虽然这表明miRNA调节通常对大脑de很重要。

Data availability

数据可用性

The raw RNA-seq data were uploaded to the Sequence Read Archive (SRA) data base under the accession number PRJNA1018560. Individual values underlying figures are provided in Supplementary data 5.

原始RNA-seq数据以登录号PRJNA018560上传到序列读取存档（SRA）数据库。补充数据5中提供了数字背后的个人价值。

Code availability

代码可用性

All analysis scripts can be obtained from the corresponding authors upon reasonable request.

所有分析脚本都可以根据合理的要求从相应的作者那里获得。

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Download referencesAcknowledgementsH.T. and S.G. acknowledge funding by the Landesinitiative Rheinland-Pfalz and the Resilience, Adaptation, and Longevity (ReALity) initiative of the Johannes Gutenberg University of Mainz. S.W. was funded by the Emergent Algorithmic Intelligence initiative of the Johannes Gutenberg University Mainz supported by the Carl-Zeiss foundation.

下载referencesAcknowledgementsH。T、 和S.G.感谢LandeInitiative Rheinland Pfalz和美因茨约翰内斯·古腾堡大学的弹性，适应和长寿（现实）倡议的资助。S、 W.由美因茨约翰内斯古腾堡大学的紧急算法智能计划资助，该计划由卡尔·蔡司基金会支持。

J.W. acknowledges funding from the Deutsche Forschungsgemeinschaft (WI-3837 / 8-1).FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthors and AffiliationsInstitute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, GermanyHristo Todorov, Stephan Weißbach, Laura Schlichtholz, Hanna Mueller, Dewi Hartwich, Susanne Gerber & Jennifer WinterInstitute of Developmental Biology and Neurobiology (iDN), Johannes Gutenberg University Mainz, Mainz, GermanyStephan WeißbachFocus Program of Translational Neurosciences, University Medical Center Mainz, Mainz, GermanyLaura SchlichtholzAuthorsHristo TodorovView author publicationsYou can also search for this author in.

J、 W.感谢Deutsche Forschungsgemeinschaft（WI-3837/8-1）的资助。资金开放获取资金由Projekt交易启用和组织。作者信息作者和附属机构约翰内斯·古腾堡大学美因茨大学医学中心人类遗传学研究所，美因茨，GermanyHristo Todorov，Stephan Weißbach，Laura Schlichtholz，Hanna Mueller，Dewi Hartwich，SusanneGerber＆Jennifer WinterInstitute of Development Biology and Neurobiology（iDN），约翰内斯Gutenberg大学美因茨，GermanyStephan Weißbach转化神经科学重点项目，美因茨大学医学中心，GermanyLaura SchlichtholzAuthorsHristo Todoroview作者出版物您也可以搜索对于本文作者。

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PubMed Google ScholarContributionsH.T., D.H., and S.W. performed the bioinformatics analysis. L.S. and H.M. performed miRNA sequencing, RT-qPCR and luciferase experiments. H.T. and J.W. wrote the manuscript. S.G. and J.W. supervised the study. All authors read and approved the final version of the manuscript.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献。T、 ，D.H.和S.W.进行了生物信息学分析。五十、 S.和H.M.进行了miRNA测序，RT-qPCR和荧光素酶实验。H、 T.和J.W.写了手稿。S、 G.和J.W.监督了这项研究。所有作者都阅读并批准了稿件的最终版本。通讯作者通讯。

Susanne Gerber or Jennifer Winter.Ethics declarations

苏珊·格伯或詹妮弗·温特。道德宣言

Competing interests

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The authors declare no competing interests.

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Ethics

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We have complied with all relevant ethical regulations for animal use. Ethical review and approval were not required for the animal study because the study did not include any animal experiments requiring approval. To carry out this study, mice were killed for organ removal. In Germany, this procedure is notifiable but does not require approval by an ethics committee..

我们遵守了动物使用的所有相关道德规范。动物研究不需要伦理审查和批准，因为该研究不包括任何需要批准的动物实验。为了进行这项研究，杀死小鼠进行器官切除。在德国，这一程序是应通报的，但不需要伦理委员会的批准。。

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Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editors: Kaliya Georgieva. A peer review file is available.

通讯生物学感谢匿名审稿人对这项工作的同行评议做出的贡献。主要处理编辑：卡莉亚·乔治耶娃。同行评审文件可用。

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Reprints and permissionsAbout this articleCite this articleTodorov, H., Weißbach, S., Schlichtholz, L. et al. Stage-specific expression patterns and co-targeting relationships among miRNAs in the developing mouse cerebral cortex.

转载和许可本文引用本文Todorov，H.，Weißbach，S.，Schlichtholz，L。等人。发育中的小鼠大脑皮层中miRNA之间的阶段特异性表达模式和共靶向关系。

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