新皮质祖细胞中BRN1和BRN2的保守转录调控驱动哺乳动物神经规范和新皮质扩张-动脉网

Conserved transcriptional regulation by BRN1 and BRN2 in neocortical progenitors drives mammalian neural specification and neocortical expansion

Nature 等信源发布 2024-09-14 12:34

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AbstractThe neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species. The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors and the emergence of indirect neurogenesis during brain evolution.

摘要由于物种间神经元亚型的数量和多样性存在巨大差异，哺乳动物新皮层的大小和复杂性各不相同。细胞多样性的增加与新皮层祖细胞库的扩大以及大脑进化过程中间接神经发生的出现相平行。

The molecular pathways that control these biological processes and are disrupted in neurological disorders remain largely unknown. Here we show that the transcription factors BRN1 and BRN2 have an evolutionary conserved function in neocortical progenitors to control their proliferative capacity and the switch from direct to indirect neurogenesis.

控制这些生物过程并在神经系统疾病中被破坏的分子途径在很大程度上仍然未知。在这里，我们显示转录因子BRN1和BRN2在新皮层祖细胞中具有进化保守功能，以控制其增殖能力以及从直接神经发生到间接神经发生的转换。

Functional studies in mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution..

对小鼠和雪貂的功能研究表明，BRN1/2与NOTCH和原发性小头畸形基因协同作用，以调节祖细胞的行为。对来自转基因猕猴的转录组学数据的分析提供了证据，表明这些分子途径在非人灵长类动物中是保守的。因此，我们的研究结果表明，BRN1/2是新皮层祖细胞中基因表达程序的中枢调节因子，对于确定进化过程中大脑的大小至关重要。。

IntroductionThe mammalian neocortex differs vastly in size and complexity between species1,2. This cellular diversity is associated with differences in the complexity of the progenitor pools that generate cortical neurons2,3,4,5,6, yet the mechanisms that lead to an increase in brain size during evolution and are disrupted in disease remain largely unknown.

引言哺乳动物新皮层的大小和复杂性在物种之间差异很大1,2。这种细胞多样性与产生皮质神经元的祖细胞池的复杂性差异有关2,3,4,5,6，然而导致进化过程中大脑大小增加并在疾病中被破坏的机制仍然很大程度上未知。

Defects in progenitor behavior have been associated to diverse neurodevelopmental disorders including microcephaly7,8,9. Mutations in genes linked to primary microcephaly, the most severe form of the disease, affect molecular pathways that regulate cell-cycle and progenitor proliferation7,9. Thus, an understanding of cortical progenitor diversity and of the mechanisms by which these progenitors self-renew and differentiate is critical to understand brain evolution and the defects in progenitor behavior that lead to neurological and psychiatric disorders.

祖细胞行为缺陷与多种神经发育障碍有关，包括小头畸形7,8,9。与原发性小头畸形（该疾病最严重的形式）相关的基因突变会影响调节细胞周期和祖细胞增殖的分子途径7,9。因此，了解皮质祖细胞的多样性以及这些祖细胞自我更新和分化的机制对于理解大脑进化以及导致神经和精神疾病的祖细胞行为缺陷至关重要。

Cortical progenitors have been broadly divided into two classes named apical progenitors (APs) that undergo mitosis in the ventricular zone (VZ), and basal progenitors (BPs) that undergo mitosis in the subventricular zone (SVZ)10,11,12,13,14. APs engage in two modes of neurogenesis termed direct and indirect neurogenesis.

皮质祖细胞大致分为两类，即在心室区（VZ）经历有丝分裂的顶端祖细胞（AP）和在心室下区（SVZ）经历有丝分裂的基底祖细胞（BP）10,11,12,13,14。AP参与两种神经发生模式，称为直接和间接神经发生。

During direct neurogenesis, APs divide asymmetrically to self-renew and to generate one neuron, while during indirect neurogenesis, APs divide asymmetrically to self-renew and generate a BP that then gives rise to neurons10,11,12,13,14. Indirect neurogenesis generates neurons for all cortical layers but is the predominant neurogenic mode that produces upper layer projection neurons (ULNs)11,12,15,16,17,18.

在直接神经发生过程中，AP不对称分裂以自我更新并产生一个神经元，而在间接神经发生过程中，AP不对称分裂以自我更新并产生BP，然后产生神经元10,11,12,13,14。间接神经发生产生所有皮质层的神经元，但是产生上层投射神经元（ULN）11,12,15,16,17,18的主要神经发生模式。

The number and complexity of ULNs have dramatically increased in gyrencephalic brains, and indirect neurogenesis is thus intricately linked to ne.

脑回大脑中ULN的数量和复杂性急剧增加，因此间接神经发生与ne错综复杂地联系在一起。

Data availability

数据可用性

The raw single cell RNA sequencing datasets generated in this study have been deposited in the GEO repository database under the accession code GSE229129. Raw single cell RNA sequencing datasets for the monkey data24 are deposited in the SRA repository database under the accession code SRP366952. All the other data generated in this study are provided in the Supplementary Information and Supplementary Data files. Source data are provided with this paper..

本研究中产生的原始单细胞RNA测序数据集已以登录号GSE229129保存在GEO存储库数据库中。猴子数据24的原始单细胞RNA测序数据集以登录号SRP366952保存在SRA存储库数据库中。本研究中产生的所有其他数据均在补充信息和补充数据文件中提供。本文提供了源数据。。

Material availability

材料可用性

All data are available in the main text or the supplementary information. Correspondence and requests for materials should be addressed to U.M.

所有数据均可在正文或补充信息中找到。信件和材料要求应寄给U.M。

Code availability

代码可用性

The code for the scRNAsequencing analysis presented in this manuscript is available on: https://doi.org/10.5281/zenodo.12582808 (https://doi.org/10.5281/zenodo.12582809).

本手稿中提供的scRNA测序分析代码可在以下网站获得：https://doi.org/10.5281/zenodo.12582808（笑声）(https://doi.org/10.5281/zenodo.12582809)。

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Download referencesAcknowledgementsWe thank members of the Müller and Kolodkin laboratories for suggestions, reagents and technical help; Alex Kolodkin, Jakub Ziak and Cristina Gil-Sanz for critical comments on the manuscript; Caiying Guo for help in generating the Brn1 floxed mice; Amanda Maxwell, Caroline Garrett and Eric Hutchinson for help with ferrets; Michele Pucak for imaging assistance; Linda Orzolek and Tyler J.

下载参考文献致谢我们感谢Müller和Kolodkin实验室的成员提供的建议，试剂和技术帮助；Alex Kolodkin，Jakub Ziak和Cristina Gil Sanz对稿件发表了批评意见；郭彩英帮助产生Brn1 floxed小鼠；阿曼达·麦克斯韦、卡罗琳·加勒特和埃里克·哈钦森为雪貂提供帮助；Michele Pucak提供成像帮助；琳达·奥尔佐莱克和泰勒·J。

Creamer for help with scRNAseq; Anna-Katerina Hadjantonakis, Connie Cepko and Raphael Kopan for plasmids; Ryoichiro Kageyama for the HES1 antibody; Andrew Holland for the γ-TUBULIN and Centrin antibodies. We are grateful to Michelle Monroe, Tajma Smith, Kaiping Zhang, Femi Cleola Villamor and Trinity Walker for assistance with mouse maintenance and genotyping.

Creamer帮助使用scRNAseq；Anna Katerina Hadjantonakis，Connie Cepko和Raphael Kopan用于质粒；Ryoichiro Kageyama用于HES1抗体；Andrew Holland用于γ-微管蛋白和中心蛋白抗体。我们感谢Michelle Monroe，Tajma Smith，张开平，Femi Cleola Villamor和Trinity Walker在小鼠维护和基因分型方面的帮助。

National Institutes of Health grant R01HG012357 and RF1MH121539 (UM); Brain Research Foundation grant BRFSG-2022-02 (B.-I.B).Author informationAuthors and AffiliationsThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USASoraia Barão, Yijun Xu, José P.

美国国立卫生研究院拨款R01HG012357和RF1MH121539（UM）；大脑研究基金会拨款BRFSG-2022-02（B.-I.B）。。

Llongueras, Rachel Vistein, Loyal Goff, Kristina J. Nielsen, Genevieve Stein-O’Brien & Ulrich MüllerDepartment of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, 06032, USAByoung-Il BaeNorthwestern University, Feinberg School of Medicine, Department of Pharmacology, Chicago, IL, 60611, USARichard S.

Llongueras，Rachel Vistein，Loyalty Goff，Kristina J.Nielsen，Genevieve Stein-O'Brien＆Ulrich Müller康涅狄格大学医学院神经科学系，法明顿，康涅狄格州，06032，美国伊利诺伊州芝加哥市范伯格医学院，美国理查德·S。

SmithDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USAChristopher A. WalshHoward Hughes Medical Institute, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USAChristopher A. WalshAuthorsSoraia BarãoView author publicationsY.

马萨诸塞州波士顿哈佛医学院波士顿儿童医院曼顿孤儿病研究中心遗传学和基因组学史密斯分部，02115，美国马萨诸塞州波士顿哈佛医学院波士顿儿童医院克里斯托弗·沃尔什·霍华德·休斯医学研究所，02115，美国克里斯托弗·A·沃尔沙索拉亚·巴若维作者出版物。

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PubMed Google ScholarContributionsConceptualization: S.B., U.M.; methodology: S.B., G.S.O’.B., Y.X., L.G., K.J.N., R.V., U.M.; investigation: S.B., Y.X., J.P.L., G.S.O’.B., U.M.; validation: S.B., Y.X., J.P.L., G.S.O’.B., U.M.; visualization: S.B.; formal analysis: S.B., Y.X., J.P.L., G.S.O’.B., U.M.; data curation: S.B., Y.X., J.P.L., G.S.O’.B.; resources: K.J.N., B.-I.B, R.S.S., C.A.W., U.M.; supervision: U.M.; project administration: U.M.; funding acquisition: U.M.; writing - original draft: S.B., U.M.; writing - review & editing: S.B., Y.X., J.P.L., L.G., K.J.N., R.V., B.-I.B., R.S.S., C.A.W., G.S.O’.B., U.M.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献概念：S.B.，U.M。；方法：S.B.，G.S.O'。B、，Y.X.，L.G.，K.J.N.，R.V.，U.M。；调查：S.B.，Y.X.，J.P.L.，G.S.O'。B、，美国。；验证：S.B.，Y.X.，J.P.L.，G.S.O'。B、，美国。；可视化：S.B。；形式分析：S.B.，Y.X.，J.P.L.，G.S.O'。B、，美国。；数据管理：S.B.，Y.X.，J.P.L.，G.S.O'。B、。；资源：K.J.N.，B.-I.B，R.S.S.，C.A.W.，U.M。；监督：U.M。；项目管理：U.M。；资金获取：U.M。；写作-原稿：S.B.，U.M。；写作-评论与编辑：S.B.，Y.X.，J.P.L.，L.G.，K.J.N.，R.V.，B.-I.B.，R.S.S.，C.A.W.，G.S.O。B、。

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Reprints and permissionsAbout this articleCite this articleBarão, S., Xu, Y., Llongueras, J.P. et al. Conserved transcriptional regulation by BRN1 and BRN2 in neocortical progenitors drives mammalian neural specification and neocortical expansion.

转载和许可本文引用本文Barão，S.，Xu，Y.，Llongeras，J.P。等人。BRN1和BRN2在新皮层祖细胞中的保守转录调控驱动哺乳动物的神经规范和新皮层扩张。

Nat Commun 15, 8043 (2024). https://doi.org/10.1038/s41467-024-52443-xDownload citationReceived: 17 November 2023Accepted: 26 August 2024Published: 14 September 2024DOI: https://doi.org/10.1038/s41467-024-52443-xShare 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.

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