ZINC FINGER PROTEINS IN EARLY KIDNEY DEVELOPMENT

肾脏早期发育中的锌指蛋白

• 批准号: 6239196
• 负责人: ERIC Grant NEILSON
• 金额: $ 15.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6239196
• 关键词: DNA binding protein; antisense nucleic acid; cell differentiation; clone cells; complementary DNA; developmental genetics; gene mutation; genetic transcription; histogenesis; immunocytochemistry; in situ hybridization; kidney; laboratory mouse; mammalian embryology; molecular cloning; northern blottings; nucleic acid sequence; oligonucleotides; protein structure; recombinant DNA; regulatory gene; renal tubule; site directed mutagenesis; transcription factor

Metanephric blastema differentiates into kidney following conversion of the nephrogenic cord by migrating ureteric bud epithelium. While various morphologic events in this process have been studied observationally, the molecular and biochemical basis for the prestructural conversion of renal mesenchyme is not known. Studies that address the transdifferentiation of renal stem cells into mature kidney are limited by a lack of known interactions that create signaling pathways. It is quite likely that steps towards terminal differentiation involve changes in protein expression in and around developing nephrons, and such changes are probably controlled by as yet undescribed genes. We hypothesize that the molecular programs determining pattern formation, spatial position, cell fate, phenotype, and structural differentiation are regulated by early sets of master genes responding to morphogenic cues. This hierarchy of genes is probably under the control of transcription factors expressing DNA-binding motifs, and the influence of these proteins over the fate of forming renal tissue is mediated through their linkage to other downstream genes producing organ differentiation. In this application we would like to identify new DNA-binding proteins that play a role in kidney development by their effects on transcription. We believe it is feasible to isolate and characterize several of these early regulatory genes using a favorite gene approach. There is evidence for the importance of zinc finger proteins in the development of nephrons in multiple species from flies forward. We propose to look for other new zinc fingers that are active in embryonic murine kidney. The murine system offers several advantages if one wishes to study higher vertebrates. Most importantly, we expect to determine the phenotype and function of some of these new finger genes by constructing targeted mutations as recombinant mice carrying null alleles, and eventually, by characterizing some of their interactions with other downstream genes. Such information will help establish new positional coordinates for transcriptional pathways in renal growth and maturation.

后肾芽基在转化成肾后分化为肾 输尿管芽上皮迁移形成肾索。虽然各种 在这个过程中的形态事件已经被观测研究， 肾前结构转换的分子和生化基础 间充质是未知的。研究表明， 肾干细胞转化为成熟的肾脏受到缺乏已知的 产生信号通路的相互作用。很有可能， 在终末分化过程中， 以及发育中的肾单位周围， 由尚未被描述的基因。 我们假设决定图案形成的分子程序， 空间位置、细胞命运、表型和结构分化是 受早期主基因组的调控，这些主基因对形态发生的线索做出反应。 这种基因的层次结构很可能是在转录的控制之下 表达DNA结合基序的因子，以及这些蛋白质的影响 肾组织形成的命运是通过它们的连接介导的， 其他产生器官分化的下游基因。 在本申请中，我们希望鉴定新的DNA结合蛋白 通过影响转录在肾脏发育中发挥作用。 我们相信分离和表征其中的几个是可行的 使用偏好基因方法的早期调控基因。有证据 锌指蛋白在肾单位发育中的重要性 从苍蝇到其他物种。我们建议寻找其他新的 锌指在小鼠胚胎肾脏中具有活性。鼠系统 如果想研究高等脊椎动物的话，最 重要的是，我们希望确定一些表型和功能， 通过构建靶向突变作为重组体， 携带无效等位基因的小鼠，最终，通过描述一些 它们与其他下游基因的相互作用。这些资料将有助 为肾细胞中转录途径建立新的位置坐标 生长和成熟。