Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA.
Development. 2020 Dec 14;147(23):dev191973. doi: 10.1242/dev.191973.
A functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules with a sequence of segments each expressing a distinct repertoire of solute transporters. The transcriptiona`l codes driving regional specification, solute transporter program activation and terminal differentiation of segment populations remain poorly understood. Here, we demonstrate that the KCTD15 paralogs and function in concert to restrict distal early (DE)/thick ascending limb (TAL) segment lineage assignment in the developing zebrafish pronephros by repressing Tfap2a activity. During renal ontogeny, expression of these factors colocalized with in distal tubule precursors. loss primed nephron cells to adopt distal fates by driving , and expression. These phenotypes were the result of Tfap2a hyperactivity, where -deficient embryos exhibited increased abundance of this transcription factor. Interestingly, reciprocally promoted and transcription, unveiling a circuit of autoregulation operating in nephron progenitors. Concomitant knockdown with overexpression further expanded the DE population. Our study reveals that a transcription factor-repressor feedback module employs tight regulation of Tfap2a and Kctd15 kinetics to control nephron segment fate choice and differentiation during kidney development.
一个功能性的脊椎动物肾脏依赖于被称为肾单位的结构单元，这些结构是具有一系列节段的上皮小管，每个节段表达一组独特的溶质转运体。驱动区域特化、溶质转运体程序激活和节段群体终末分化的转录编码仍然知之甚少。在这里，我们证明 KCTD15 基因家族的成员 和 协同作用，通过抑制 Tfap2a 的活性来限制斑马鱼胚胎肾原基中远端早期（DE）/厚升支（TAL）节段谱系的分配。在肾发生过程中，这些因子的表达与远端小管前体中的 共定位。 的缺失通过驱动 、 和 的表达，使肾单位细胞向远端命运分化。这些表型是 Tfap2a 过度活跃的结果，其中 -缺陷型胚胎中这种转录因子的丰度增加。有趣的是， 反过来促进了 和 的转录，揭示了在肾祖细胞中起作用的自我调节回路。与 过表达同时敲低 进一步扩大了 DE 群体。我们的研究揭示了一个转录因子-抑制剂反馈模块，通过严格控制 Tfap2a 和 Kctd15 的动力学来控制肾脏发育过程中肾单位节段命运的选择和分化。
