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

摘要： Etv 4和Etv 5（Etv 4/5）是在发育中的小鼠肾脏中表达的两种转录因子，特别是在发育中的小鼠肾脏中。 输尿管芽尖、后肾间充质和肾泡。 我们的初步数据使用了肾单位祖细胞（NPC）中Etv 4/5缺失的小鼠模型， 后代显示这些转录因子在肾发生中的关键作用; Etv 4/5的缺失 导致NPC过早衰竭、生肾区变薄和出生时肾发育不全/囊性。在 此外，这些突变体早在s形体阶段就存在分割缺陷。我们已经生成 来自NPC突变体和同窝对照胚胎肾的RNAseq数据，并将Wnt 4鉴定为下游转录因子。 Etv 4/5的目标。 基于这些初步数据，我们假设Etv 4/5至少部分地通过以下途径调节肾发生： 下调NPC和发育中的肾单位中的Wnt信号。我们进一步假设， 需要下调以有利于NPC的自我更新和早期肾单位的分化。 我们将在两个目标中检验这些假设。在目标一中，我们将研究Fgfs、Etv 4/5之间的串扰 和Wnt 4信号传导以促进NPC的自我更新/防止NPC的分化。在目标二中，我们将研究 Etv 4/5和Wnt 4信号传导如何影响肾单位分化。这些研究将进一步深入了解 信号网络驱动祖细胞自我更新和分化;他们也将扩大我们的知识， Etv 4和Etv 5表达的细胞读数，因此不仅对免疫学领域具有显著影响， 发育生物学以及癌症和体外器官形成。

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.