Identification of genetic pathways that regulate kidney cell fate: Hand2 inhibits intermediate mesoderm development

鉴定调节肾细胞命运的遗传途径：Hand2抑制中间中胚层发育

• 批准号: 10668891
• 负责人: Elliot A Perens
• 金额: $ 5.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668891
• 关键词: Address; Advisory Committees; Animal Model; Bilateral; California; Candidate Disease Gene; Cells; Child; Childhood; Chronic Kidney Failure; Clinical; Comprehension; Congenital Abnormality; Data; Development; Diagnostic; Dimerization; Embryo; Endothelium; Equilibrium; Etiology; Genes; Genetic; Genetic Medicine; Goals; Human Genetics; Hypertension; Individual; Intermediate Mesoderm; Kidney; Kidney Diseases; Laboratories; Laboratory Research; Lateral; Light; Maps; Mentors; Mesoderm; Modeling; Mosaicism; Nephrology; Optics; Organ; Organism; Pathway interactions; Patient-Focused Outcomes; Patients; Physicians; Play; Population; Principal Investigator; Production; Protocols documentation; Regenerative Medicine; Regulation; Research; Research Training; Resolution; Role; Scientist; Signal Pathway; Signal Transduction; Specialist; Techniques; Testing; Therapeutic; Training; Universities; Urinary tract; Urinary tract infection; Veins; Venous; Work; Zebrafish; Zinc Fingers; cell type; congenital anomalies of the kidney; disease-causing mutation; experimental study; genetic analysis; high risk; improved; improved outcome; insight; kidney cell; mutant; nephrogenesis; overexpression; progenitor; prognostic; stem cell technology; stem cells; transcription factor; transcriptome

PROJECT SUMMARY The Principal Investigator seeks mentored training to investigate the genetic regulation of early kidney development using the zebrafish embryo. Research and training will be carried out in the laboratory of Dr. Deborah Yelon, with the support of the Division of Pediatric Nephrology at the University of California, San Diego and an advisory committee composed of specialists in kidney development and disease and in the genetic regulation of organ formation. The objective is to obtain training and pursue laboratory research that will lead to the Principal Investigator's development into an independent physician-scientist. The overall goal of the research is to elucidate the genetic pathways regulating early stages of kidney development in order to gain insight into the etiology of kidney birth defects and to instruct strategies in regenerative medicine. To do so, the PI will take advantage of the genetic and embryological benefits of using the zebrafish as a model organism. Like mammalian kidneys, zebrafish kidneys are derived from the intermediate mesoderm (IM). Work in multiple organisms, including zebrafish, has defined several conserved factors that promote IM formation. However, the mechanisms defining the boundaries that distinguish the IM from its neighboring territories are not yet understood. Recent studies by the PI suggest that the bHLH transcription factor Hand2 defines the lateral border of the IM by regulating cell fate decisions within the posterior mesoderm. While the IM and embryonic kidney are expanded in hand2 mutants, hand2 overexpression results in strong inhibition of IM and kidney development. Additionally, hand2 is expressed in a portion of the posterior mesoderm that lies laterally adjacent to the IM. Venous progenitors arise between these two territories, and hand2 promotes venous progenitor development while inhibiting IM formation at this interface. The lateral hand2-expressing territory also expresses osr1, a zinc-finger transcription factor previously implicated in promoting kidney formation, and genetic analyses suggest that hand2 and osr1 have functionally antagonistic roles during kidney development. Together, these data shed light on a previously unrecognized genetic network that regulates IM boundaries, suggesting a model in which hand2 functions in opposition to osr1 to control the allocation of progenitor cells to kidney and vein lineages. To test this model, two specific aims will be pursued. The first aim will define the role of hand2 in the inhibition of IM lineage specification, using high-resolution fate map analysis and cell autonomy studies. The second aim will identify genes in the pathways through which hand2 and osr1 control IM specification, using complementary candidate gene and whole transcriptome approaches to identify relevant partner and effector genes. These studies will elucidate the role of hand2 in IM formation and illuminate the pathways that define the boundaries of the IM by balancing formation of the kidney and vein lineages. Over the long term, detailed comprehension of these genetic pathways should improve diagnostic, prognostic, and therapeutic options for patients with kidney disease.

项目摘要 主要研究者寻求指导培训，以调查早期肾脏疾病的遗传调控 利用斑马鱼胚胎进行发育。研究和培训将在博士的实验室进行。 Deborah Yelon在旧金山加州大学儿科肾病学分部的支持下， 迭戈和一个由肾脏发育和疾病专家组成的咨询委员会， 器官形成的遗传调控。目标是获得培训和进行实验室研究， 将使主要研究者发展成为独立的医生-科学家。的总目标 这项研究旨在阐明调节肾脏发育早期阶段的遗传途径， 深入了解肾脏出生缺陷的病因，并指导再生医学的策略。做 因此，PI将利用斑马鱼作为模型的遗传和胚胎学优势 有机体与哺乳动物的肾脏一样，斑马鱼的肾脏也来源于中间中胚层（IM）。工作 在包括斑马鱼在内的多种生物体中，已经确定了几种促进IM形成的保守因子。 然而，定义将IM与其相邻领土区分开的边界的机制是 还不明白。PI最近的研究表明，bHLH转录因子Hand 2定义了 通过调节后中胚层内的细胞命运决定来调节IM的外侧边缘。虽然IM和 胚胎肾在hand 2突变体中扩增，hand 2过表达导致IM的强烈抑制， 肾脏发育此外，hand 2在位于外侧的后中胚层的一部分中表达， 与IM相邻。静脉祖细胞在这两个区域之间产生，并且hand 2促进静脉祖细胞的形成。 祖细胞发育，同时抑制该界面处的IM形成。侧手2-表达领域 还表达osr 1，一种先前参与促进肾脏形成的锌指转录因子， 遗传分析表明，Hand 2和OSR 1在肾脏发育过程中具有功能上的拮抗作用。 总之，这些数据揭示了一个以前未被认识到的调节IM边界的遗传网络， 提示了一种模型，其中Hand 2与OSR 1相反地起作用以控制祖细胞的分配， 肾脏和静脉谱系。为了检验这一模式，将追求两个具体目标。第一个目标将确定作用 使用高分辨率命运图分析和细胞自主性， 问题研究第二个目标是鉴定hand 2和osr 1控制IM的途径中的基因 特异性，使用互补候选基因和全转录组方法来鉴定相关的 伴侣和效应基因。这些研究将阐明hand 2在IM形成中的作用，并阐明其在IM形成中的作用。 通过平衡肾脏和静脉谱系的形成来定义IM边界的途径。来 对这些遗传通路的长期、详细的了解将有助于提高诊断、预后和 肾病患者的治疗选择。

项目成果

Genomic sequencing has a high diagnostic yield in children with congenital anomalies of the heart and urinary system.

• DOI: 10.3389/fped.2023.1157630
• 发表时间: 2023
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6

osr1 couples intermediate mesoderm cell fate with temporal dynamics of vessel progenitor cell differentiation.

osr1 将中间中胚层细胞命运与血管祖细胞分化的时间动态耦合起来。

• DOI: 10.1242/dev.198408
• 发表时间: 2021
• 期刊: Development (Cambridge, England)
• 作者: Perens,ElliotA;Diaz,JessykaT;Quesnel,Agathe;Askary,Amjad;Crump,JGage;Yelon,Deborah
• 通讯作者: Yelon,Deborah

Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm.

Hand2 抑制肾脏规格，同时促进后中胚层内的静脉形成。

• DOI: 10.7554/elife.19941
• 发表时间: 2016
• 期刊: eLife
• 影响因子: 7.7
• 作者: Perens,ElliotA;Garavito-Aguilar,ZayraV;Guio-Vega,GinaP;Peña,KarenT;Schindler,YochevedL;Yelon,Deborah
• 通讯作者: Yelon,Deborah