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
基本信息
- 批准号:10655102
- 负责人:
- 金额:$ 46.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAutomobile DrivingBirthCell Differentiation processCell MaintenanceCellsCystic kidneyDataDefectDevelopmentDevelopmental BiologyDistalDoseDown-RegulationETV4 geneEmbryoEmbryonic DevelopmentEpitheliumEquilibriumFibroblast Growth FactorGenetic TranscriptionHistologyHumanImmunofluorescence ImmunologicIn VitroIndividualInvadedKidneyKnowledgeLimb structureLinkLoxP-flanked alleleLungMalignant NeoplasmsMediatingMesenchymeMetanephric DiverticulumModelingMusNeoplasm MetastasisNephronsObesityOrganogenesisPathway interactionsPregnancyRegulationRoleShapesSignal PathwaySignal TransductionTamoxifenTestingTestisTherapeutic InterventionThinnessTissuesTranscription RepressorTubular formationUndifferentiatedUp-RegulationVesicleWNT Signaling PathwayWNT4 genebeta catenincell motilityconfocal imagingexhaustexhaustionglial cell-line derived neurotrophic factorinsightmigrationmotor neuron developmentmouse modelmutantnephrogenesisnephron progenitornovelpostnatalprematurepreventprogenitorself-renewalsingle-cell RNA sequencingstem cellsstemnesstranscription factortranscriptome sequencingtumor progression
项目摘要
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。
项目成果
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Cristina Cebrian Ligero其他文献
Cristina Cebrian Ligero的其他文献
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