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

摘要： ETV4和ETV5(ETV4/5)是两种转录因子，在发育中的小鼠肾脏中表达，特别是在 输尿管芽尖、后肾间充质和肾小泡。 我们的初步数据使用了小鼠肾单位祖细胞(NPC)和它们的ETV4/5缺失模型 子代显示这些转录因子在肾脏形成过程中起关键作用；缺失ETV4/5 导致鼻咽癌过早衰竭，生肾区变薄，出生时肾脏发育不良/囊性。在……里面 此外，这些突变体早在S体型阶段就出现了分割缺陷。我们已经产生了 来自NPC突变体和斜发对照胚胎肾脏的RNAseq数据和确定Wnt4为下游 ETV4/5的目标。 根据这些初步的数据，我们假设ETV4/5至少部分地通过 下调鼻咽癌和发育中肾单位中的Wnt信号。我们进一步假设这一点 需要下调以促进神经前体细胞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FGF4/5之间的串扰 和WNT4信号，以促进自我更新/防止NPC分化。在第二个目标中，我们将调查 ETV4/5和WNT4信号通路如何影响肾单位分化。这些研究将进一步深入了解 信令网络驱动先行者自我更新和差异化；他们也将扩大我们对 细胞读出ETV4和ETV5的表达，因此不仅对领域有重大影响 发育生物学，也研究癌症和体外器官发生。

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.