Esco2黏连蛋白病小鼠模型中的肢体减少是由p53依赖性凋亡和血管破坏介导的-动脉网

Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption

Nature 等信源发布 2024-08-21 18:30

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AbstractRoberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis.

摘要罗伯茨综合征（RBS）是一种常染色体隐性遗传疾病，由ESCO2功能丧失变异引起严重的生长缺陷和肢体减少。在这里，我们阐明了Esco2fl/fl肢体减少的发病机理；在胚胎发生过程中使用体细胞和单细胞RNA-seq和基因共表达网络分析的Prrx1-CreTg/0小鼠模型。

Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo.

我们的结果揭示了形态和血管缺陷，最终导致E12.5突变肢体出血。这种异常发育进程的基础是凋亡前的间充质细胞群，该细胞群特异于突变肢芽，从E9.5开始富含p53相关信号传导。然后，我们表征了体内细胞周期停滞，DNA损伤，细胞死亡和炎症性白三烯信号通路的这些p53相关过程。

In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions..

在子宫内用p53抑制剂pifithrin-α治疗可以挽救突变肢体的出血。最后，在与RBS，沙利度胺胚胎病和其他遗传性肢体减少疾病相关的基因中发现了显着的富集，表明这些疾病中存在常见的血管病因。。

IntroductionCohesinopathies are a group of genetic disorders caused by pathogenic variants in genes encoding the cohesin subunits or their various regulators that participate in chromosome segregation and gene transcription1,2,3,4. These disorders are heterogeneous and include Roberts syndrome (RBS) and Cornelia de Lange syndrome, as well as CHOPS, chronic atrial and intestinal dysrhythmia, holoprosencephaly 13, intellectual disability-hypotonic facies, and Warsaw breakage syndromes4,5,6,7,8,9.

引言粘着蛋白病是由编码粘着蛋白亚基的基因或其参与染色体分离和基因转录的各种调节因子的致病变异引起的一组遗传疾病1,2,3,4。这些疾病是异质性的，包括罗伯茨综合征（RBS）和Cornelia de Lange综合征，以及CHOPS，慢性心房和肠道节律失常，全前脑13，智力障碍低渗相和华沙断裂综合征4,5,6,7,8,9。

Among the most severe is RBS, a monogenic disorder with an autosomal recessive pattern of inheritance caused by loss-of-function (LOF) pathogenic variants in the Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2 (ESCO2) gene, which encodes a regulator of the cohesin complex7,10,11.Infants with RBS experience profound growth deficiency of prenatal onset and present with various congenital anomalies, most notably with phocomelia or severe limb reduction, and craniofacial abnormalities10,12,13,14.

其中最严重的是RBS，这是一种具有常染色体隐性遗传模式的单基因疾病，由姐妹染色单体内聚N-乙酰转移酶2（ESCO2）基因的建立中的功能丧失（LOF）致病变异引起，该基因编码粘着蛋白复合物的调节剂7,10,11。患有RBS的婴儿在产前发作时会出现严重的生长缺陷，并伴有各种先天性异常，最明显的是phocomelia或严重的肢体减少以及颅面异常10,12,13,14。

There is phenotypic variability between cases with a positive correlation of severity between the craniofacial abnormalities and the limb reduction5,8,14. The most striking clinical presentation includes complete, bilateral symmetric reduction of the limbs, while less severe cases exhibit hypomelia due to mesomelic or rhizomelic shortening12,14.

颅面异常与肢体缩小之间的严重程度呈正相关的病例之间存在表型变异[5,8,14]。最引人注目的临床表现包括四肢完全双侧对称复位，而较不严重的病例由于中胚层或根茎缩短而表现出hypomelia12,14。

Typically, the upper and lower limb reduction or absence are accompanied by digit malformations, often presenting with oligodactyly, thumb aplasia or hypoplasia, syndactyly, clinodactyly, and elbow and knee flexion contractures12,14. Given the syndromic nature of the disease, survival is poor beyond the neonatal period, although mild cases can survive into adulthood with varying degrees of physical and intellectual disability.

通常，上肢和下肢的减少或缺失伴有手指畸形，通常表现为少指畸形，拇指发育不全或发育不全，并指畸形，斜指畸形以及肘部和膝关节屈曲挛缩12,14。鉴于该疾病的综合征性质，新生儿期以后的生存率很低，尽管轻度病例可以存活到成年，并伴有不同程度的身体和智力残疾。

The ph.

ph。

Esco2

埃斯科2

fl/fl;Prrx1-Cre

in/fl；Prrx1 Cre

Tg/0 mouse model resembles the human RBS limb phenotypeTo study the function of ESCO2 in the context of limb development, we generated an Esco2fl/fl conditional knockout (CKO) mouse line bred with Prrx1-CreTg/0 to preferentially eliminate Esco2 from limb mesenchyme. We introduced a deletion in exon 4 resulting in a premature stop codon, replicating the effect of a documented human pathogenic variant in ESCO2 (c.879_880delAG (p.D292fsX47); ClinVar ID: 21250) that is predicted to produce a truncated Esco2 transcript with nonsense-mediate decay (Supplementary Fig. 1a–c)10.

Tg/0小鼠模型类似于人类RBS肢体表型为了研究ESCO2在肢体发育中的功能，我们产生了用Prrx1-CreTg/0繁殖的Esco2fl/fl条件性敲除（CKO）小鼠系，以优先消除肢体间充质中的ESCO2。我们在第4外显子中引入了一个缺失，导致终止密码子过早，复制了ESCO2中已记录的人类致病变异的作用（c.879Ͱu 880delAG（p.D292fsX47）；ClinVar ID:21250），预计会产生无义介导衰变的截短的Esco2转录本（补充图1a–c）10。

The first appearance of the limb buds and the activity of Prrx1-induced Cre recombinase are observed at E9.550. Prrx1 is expressed in a proportion of forelimb mesenchymal cells and completes recombination in all forelimb mesenchymal cells at E10.5.While most developing Esco2fl/fl;Prrx1-CreTg/0 embryos resulted in perinatal lethality, some were livebirths.

在E9.550处观察到肢芽的首次出现和Prrx1诱导的Cre重组酶的活性。Prrx1在一定比例的前肢间充质细胞中表达，并在E10.5时在所有前肢间充质细胞中完成重组。而大多数发育中的Esco2fl/fl；Prrx1-CreTg/0胚胎导致围产期致死率，其中一些是活产。

Esco2fl/fl;Prrx1-CreTg/0 pups at P0 were born with striking limb reduction that resembled the human RBS phenotype (Fig. 1a). This deletion was highly penetrant with 100% of n = 120 Esco2fl/fl;Prrx1-CreTg/0 embryos displaying the RBS limb phenotype (Fig. 1a). Post-mortem autopsy analysis of mutants revealed islands of disorganized chondrocytes and poorly developed chondroid matrix compared to controls (Fig. 1b).

Esco2fl/fl；P0的Prrx1-CreTg/0幼崽出生时肢体明显减少，类似于人类RBS表型（图1a）。；Prrx1-CreTg/0胚胎显示RBS肢体表型（图1a）。与对照组相比，对突变体的尸检分析显示，软骨细胞岛杂乱无章，软骨样基质发育不良（图1b）。

The long bones of the fore- and hindlimbs were unidentifiable, with loose mesenchyme replacing skeletal muscle around the bones (Fig. 1b, Supplementary Fig. 1d, e). Internal organs were not significantly affected where Prrx1 was not expressed51,52 (Fig. 1a).Fig. 1: Esco2fl/fl;Prrx1-CreTg/0 mouse model of Roberts syndrome.a P0 mice in dorsal and lateral views with indicated genotypes.

前肢和后肢的长骨无法识别，松散的间充质替代了骨骼周围的骨骼肌（图1b，补充图1d，e）。没有表达Prrx1的内部器官没有受到显着影响51,52（图1a）。图1:Esco2fl/fl；罗伯茨综合征的Prrx1-CreTg/0小鼠模型。具有指定基因型的背侧和侧视图中的P0小鼠。

Mutant mice present with phocomelia and craniofacial abnormalit.

突变小鼠出现phocomelia和颅面异常。

Injections of pifithrin-α were administered according to Jones et al.56. Pifithrin-α (Enzo, BML-GR325-0005) was injected intraperitoneally at 2.2 mg per kg (body weight) in PBS. Female mice were weighed daily to determine the necessary dosage. Treatment was daily from E8.5 until the embryos were harvested at E11.5 or E12.5, and subsequently analyzed.Gene enrichment analysisA literature search was performed using PubMed and OMIM to identify genes implicated in genetic disorders that cause with limb reduction and thalidomide embryopathy.

根据Jones等人56注射pifithrin-α。在PBS中以2.2mg/kg（体重）腹膜内注射Pifithrin-α（Enzo，BML-GR325-0005）。每天称重雌性小鼠以确定必要的剂量。从E8.5开始每天进行处理，直到在E11.5或E12.5收获胚胎，然后进行分析。基因富集分析使用PubMed和OMIM进行文献检索，以鉴定与导致肢体减少和沙利度胺胚胎病的遗传疾病有关的基因。

A total of 326 genes were collectively identified and used for the enrichment analysis (designated gene_list). Genes were converted to their mouse orthologs using babelgene package in R. Differentially expressed genes from E9.5 determined by scRNA-seq analysis were tested for significant (p ≤ 0.05) gene set enrichment against gene_list.

共鉴定出326个基因，并将其用于富集分析（指定为gene\u列表）。。

Fisher’s exact tests with a Bonferroni correction applied for multiple comparisons testing was applied.Other statistical analyzesAnalyzes determining statistical significance between Esco2fl/fl and Esco2fl/fl;Prrx1-CreTg/0 samples for TUNEL assays, number of branch points, and blood vessel diameter were performed using a Student’s t-test in Microsoft Excel.Reporting summaryFurther information on research design is available in the Nature Portfolio Reporting Summary linked to this article..

应用具有Bonferroni校正的Fisher精确检验进行多重比较检验。其他统计分析分析确定Esco2fl/fl和Esco2fl/fl之间的统计显着性；使用Microsoft Excel中的学生t检验进行用于TUNEL分析的Prrx1-CreTg/0样品，分支点数和血管直径。报告摘要有关研究设计的更多信息，请参阅本文链接的Nature Portfolio Reporting Summary。。

Data availability

数据可用性

The data generated in this study have been deposited in the Gene Expression Omnibus under the GEO accession number GSE230493 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE101099]. The processed data are available in the supplementary datasets within the article. All other relevant data supporting the key findings of this study are available within the article and its Supplementary Information files or from the corresponding author upon request. Source data are provided with this paper..

这项研究产生的数据已保存在GEO登录号GSE230493的Gene Expression Omnibus中[https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE101099]。处理后的数据可在本文的补充数据集中找到。支持本研究主要发现的所有其他相关数据均可在文章及其补充信息文件中获得，或应要求从通讯作者处获得。本文提供了源数据。。

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Download referencesAcknowledgementsWe would like to thank our colleagues at Mount Sinai’s Microscopy CoRE and CCMS’s Necroscopy core. This work was supported, in part, through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.

下载参考文献致谢我们要感谢西奈山显微镜核心和CCMS坏死镜核心的同事。这项工作部分得到了西奈山伊坎医学院科学计算所提供的计算资源和员工专业知识的支持。

Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health (NIH) under award number S10OD026880 and NIH grants R01AG068030 (B.Z.), R03DE026814 (E.J and B.Z.), R01DE029832 (E.J. and H.B.), and R01DE029322 (E.J. and H.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Author informationAuthors and AffiliationsDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L.

本文报道的研究得到了美国国立卫生研究院（NIH）研究基础设施办公室的支持，奖项编号为S10OD026880，NIH拨款R01AG068030（B.Z.），R03DE026814（E.J和B.Z.），R01DE029832（E.J.和H.B.）和R01DE029322（E.J.和H.B.）。内容完全由作者负责，不一定代表美国国立卫生研究院的官方观点。作者信息作者和附属机构西奈山伊坎医学院遗传学和基因组科学系，古斯塔夫L。

Levy Place, New York, NY, USAArielle S. Strasser, Ana Silvia Gonzalez-Reiche, Xianxiao Zhou, Braulio Valdebenito-Maturana, Xiaoqian Ye, Bin Zhang, Meng Wu, Harm van Bakel & Ethylin Wang JabsMount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L.

Levy Place，纽约州纽约市，USAArielle S.Strasser，Ana Silvia Gonzalez Reiche，Xianxiao Zhou，Braulio Valdebenito Maturana，Xiaoqian Ye，Bin Zhang，Meng Wu，Harm van Bakel＆Ethylin Wang JabsMount西奈山伊坎医学院西奈转化性疾病建模中心，One Gustave L。

Levy Place, New York, NY, USAXianxiao Zhou & Bin ZhangDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USABin ZhangDepartment of Clinical Genomics, Mayo Clinic, 200 First Street, Rochester, MN, USAMeng Wu & Ethylin Wang JabsDepartment of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street, Rochester, MN, USAMeng Wu & Ethylin Wang JabsIcahn Genomics Institute, Icahn School of Medicine at Mount Sinai, One Gustave L.

利维广场，纽约，纽约，USAXianxiao Zhou＆Bin Zhang西奈山伊坎医学院药理科学系，一个Gustave L.利维广场，纽约，纽约，USABin Zhang，梅奥诊所临床基因组学系，200 First Street，Rochester，MN，USAMeng Wu＆Ethylin Wang Jabsecahn生物化学与分子生物学系，梅奥诊所，200 First Street，Rochester，MN，USAMeng Wu＆Ethylin Wang JabsIcahn Genomics Institute，西奈山伊坎医学院，一个Gustave L。

Levy Place, New York, NY, USAHarm van BakelDepartment of Microbiology, Icahn School of Medicine .

。

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PubMed Google ScholarContributionsX.Y. developed and implemented LoxP-Cre strategies for creating the Esco2 CKO mouse model. M.W. and A.S.S. characterized the mouse model. A.S.G.R. and A.S.S. conducted the bulk and single-cell RNA-seq analyzes. B.V-M. conducted the InferCNV analysis, trajectory and RNA velocity analyzes and assisted with single-cell RNA-seq analyzes.

PubMed谷歌学术贡献x。Y、开发并实施了LoxP-Cre策略，用于创建Esco2 CKO小鼠模型。M、 W.和A.S.S.对小鼠模型进行了表征。A、 S.G.R.和A.S.S.进行了大量和单细胞RNA-seq分析。B、 V-M.进行了InferCNV分析，轨迹和RNA速度分析，并辅助了单细胞RNA-seq分析。

X.Z., B.Z., and A.S.S. conducted the gene co-expression network and drug repositioning analyzes. A.S.S., M.W. completed all wet-lab related experimentation. A.S.S. generated all the figures and tables for the manuscript with input from H.v.B. and E.W.J. A.S.S. wrote the initial manuscript draft with input and suggestions from H.v.B.

十、 Z.，B.Z。和A.S.S.进行了基因共表达网络和药物重新定位分析。A、 S.S.，M.W.完成了所有与湿实验室相关的实验。A、 S.S.根据H.v.B.的输入生成了稿件的所有图表，E.W.J.A.S.S.根据H.v.B.的输入和建议撰写了稿件初稿。

and E.W.J. H.v.B and E.W.J provided advice and guidance throughout. All the authors contributed to editing and revising the paper.Corresponding authorsCorrespondence to.

E.W.J.H.v.B和E.W.J自始至终都提供了建议和指导。所有作者都为编辑和修订论文做出了贡献。通讯作者通讯。

Meng Wu, Harm van Bakel or Ethylin Wang Jabs.Ethics declarations

孟武，哈姆·范巴克尔或伊瑟林·王刺拳。道德宣言

Competing interests

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The authors declare no competing interests.

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Nature Communications thanks Katta Girisha, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Nature Communications感谢Katta Girisha和另一位匿名审稿人对这项工作的同行评审所做的贡献。同行评审文件可用。

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Reprints and permissionsAbout this articleCite this articleStrasser, A.S., Gonzalez-Reiche, A.S., Zhou, X. et al. Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.

转载和许可本文引用本文Strasser，A.S.，Gonzalez-Reiche，A.S.，Zhou，X。等人。Esco2粘着蛋白病小鼠模型中的肢体减少是由p53依赖性细胞凋亡和血管破坏介导的。

Nat Commun 15, 7154 (2024). https://doi.org/10.1038/s41467-024-51328-3Download citationReceived: 01 September 2023Accepted: 01 August 2024Published: 21 August 2024DOI: https://doi.org/10.1038/s41467-024-51328-3Share 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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血管生成计算生物学和生物信息学发展基因表达遗传模型

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