Role of Etv4 and Etv5 in the self-renewal and differentiation of nephron progenitors

Etv4和Etv5在肾单位祖细胞自我更新和分化中的作用

• 批准号: 10655102
• 负责人: Cristina Cebrian Ligero
• 金额: $ 46.03万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655102
• 关键词: Address; Affect; Automobile Driving; Birth; Cell Differentiation process; Cell Maintenance; Cells; Cystic kidney; Data; Defect; Development; Developmental Biology; Distal; Dose; Down-Regulation; ETV4 gene; Embryo; Embryonic Development; Epithelium; Equilibrium; Fibroblast Growth Factor; Genetic Transcription; Histology; Human; Immunofluorescence Immunologic; In Vitro; Individual; Invaded; Kidney; Knowledge; Limb structure; Link; LoxP-flanked allele; Lung; Malignant Neoplasms; Mediating; Mesenchyme; Metanephric Diverticulum; Modeling; Mus; Neoplasm Metastasis; Nephrons; Obesity; Organogenesis; Pathway interactions; Pregnancy; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Tamoxifen; Testing; Testis; Therapeutic Intervention; Thinness; Tissues; Transcription Repressor; Tubular formation; Undifferentiated; Up-Regulation; Vesicle; WNT Signaling Pathway; WNT4 gene; beta catenin; cell motility; confocal imaging; exhaust; exhaustion; glial cell-line derived neurotrophic factor; insight; migration; motor neuron development; mouse model; mutant; nephrogenesis; nephron progenitor; novel; postnatal; premature; prevent; progenitor; self-renewal; single-cell RNA sequencing; stem cells; stemness; transcription factor; transcriptome sequencing; tumor progression

Abstract: Etv4 and Etv5 (Etv4/5) are two transcription factors expressed in the developing mouse kidney, specifically in the ureteric bud tips, the metanephric mesenchyme and the renal vesicle. Our preliminary data using a mouse model of Etv4/5 deletion in the nephron progenitor cells (NPCs) and their progeny demonstrate a critical role for these transcription factors during nephrogenesis; absence of Etv4/5 cause premature NPC exhaustion, thinning nephrogenic zone and hypoplastic/cystic kidneys at birth. In addition, these mutants present segmentation defects as early as the s-shape body stage. We have generated RNAseq data from NPC mutant and littermate control embryonic kidneys and identified Wnt4 as a downstream target of Etv4/5. Based on these preliminary data we hypothesize that Etv4/5 modulate nephrogenesis, at least in part, by downregulating Wnt signaling in the NPCs and in the developing nephron. We further hypothesize that this downregulation is required to favor both self-renewal of NPCs and differentiation of the early nephron. We will test these hypotheses in two aims. In aim one we will investigate the crosstalk between Fgfs, Etv4/5 and Wnt4 signaling to promote self-renewal/prevent differentiation of the NPCs. In aim two we will investigate how Etv4/5 and Wnt4 signaling affect nephron differentiation. These studies will provide further insight into the signaling network driving progenitor self-renewal and differentiation; they will also expand our knowledge of the cellular readout of Etv4 and Etv5 expression, therefore having a significant impact not only on the field of developmental biology but also in cancer and in vitro organogenesis.

抽象的： Etv4 和 Etv5 (Etv4/5) 是在发育中的小鼠肾脏中表达的两种转录因子，特别是在 输尿管芽尖、后肾间质和肾囊泡。 我们的初步数据使用肾单位祖细胞 (NPC) 中 Etv4/5 缺失的小鼠模型及其 后代证明这些转录因子在肾发生过程中发挥着关键作用；缺少 Etv4/5 导致 NPC 过早衰竭、肾源区变薄以及出生时肾发育不全/囊性。在 此外，这些突变体早在S形身体阶段就出现了分割缺陷。我们已经生成了 来自 NPC 突变体和同窝对照胚胎肾脏的 RNAseq 数据，并将 Wnt4 确定为下游 Etv4/5 的目标。 基于这些初步数据，我们假设 Etv4/5 至少部分地通过以下方式调节肾发生： 下调 NPC 和发育中肾单位中的 Wnt 信号传导。我们进一步假设这 需要下调以促进 NPC 的自我更新和早期肾单位的分化。 我们将在两个目标上检验这些假设。在目标一中，我们将研究 Fgfs、Etv4/5 之间的串扰 Wnt4 信号传导促进 NPC 的自我更新/防止分化。在目标二中我们将调查 Etv4/5 和 Wnt4 信号传导如何影响肾单位分化。这些研究将提供进一步的见解 驱动祖细胞自我更新和分化的信号网络；他们还将扩大我们的知识 Etv4 和 Etv5 表达的细胞读数，因此不仅对领域产生重大影响 发育生物学以及癌症和体外器官发生。