Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation

肾单位祖细胞自我更新和分化的调节

基本信息

批准号：
9607382
负责人：
MICHAEL I RAUCHMAN
金额：
$ 20.12万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9607382
关键词：
Regulation Nephron Progenitor Cell Self

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the proposed work is to determine how the Sall1 transcription factor and its associated chromatin remodeling complexes control gene regulation to generate a normal endowment of nephrons. This will illuminate mechanisms that underlie human genetic syndromes and common sporadic birth defects, such as renal hypoplasia (small kidneys with reduced numbers of nephrons), which result in kidney failure. Formation of the proper complement of nephrons requires a balance between expansion of multi-potent renal progenitor cells and differentiation. Genetic deficiency of Sall1 alters gene expression in the developing kidney, accelerating nephron differentiation leading to a depletion of nephron progenitor cells and renal hypoplasia. These uncommitted nephron precursors, termed cap mesenchyme, must respond to canonical Wnt/ß-catenin signals by either undergoing self-renewal or mesenchymal-to-epithelial transition to form most tubular segments of the nephron. The transcriptional mechanisms that control these opposing responses of the cap mesenchyme are not known, but current evidence argues that Sall1 is pivotal in this critical developmental decision. Our recent studies provide evidence for a novel paradigm. We propose that Sall1 cooperates with the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex, to determine nephron progenitor cell fate by regulating the transcriptional output in response to Wnt/ß-catenin. This application will test key predictions of this model using a combination of genetic, genomic, and biochemical approaches. Six2 is an inhibitor of nephron differentiation. In Aim 1, we will determine if Sall1 directly up-regulates Six2 expression in cap mesenchyme to restrain differentiation of progenitor cells. Expression of Wnt9b, the main differentiation signal, is increased in Sall1 mutants. We will determine if the combination of increased Wnt9b and reduced Six2 expression are sufficient to cause accelerated nephron formation, and exhaustion of self-renewing progenitor cells. Aim 2 will determine how Sall1 and NuRD control the transcriptional output in nephron progenitor cells to determine whether the uncommitted precursor cells undergo self-renewal or initiate nephron differentiation. The mechanistic insights gained from these studies will advance efforts to propagate nephron progenitors in vitro and/or promote regeneration of mature tubular epithelial cells in order to correct nephron deficits.

描述（由申请人提供）：拟议工作的长期目标是确定 Sall1 转录因子及其相关染色质重塑复合物如何控制基因调控以产生肾单位的正常禀赋，这将阐明人类遗传综合征的机制。以及常见的散发性出生缺陷，例如肾发育不全（肾单位数量减少的小肾脏），这会导致肾单位的适当补充的形成。需要多能肾祖细胞的扩增和分化之间的平衡。Sall1 的遗传缺陷会改变发育中肾脏的基因表达，加速肾单位分化，导致肾单位祖细胞耗竭和肾发育不全。，必须通过自我更新或间充质到上皮细胞的转变来响应典型的 Wnt/ß-catenin 信号控制帽间充质的这些相反反应的转录机制尚不清楚，但目前的证据表明 Sall1 在这一关键的发育决定中至关重要，我们提出了一种新的范例。 Sall1 与核小体重塑和脱乙酰酶 (NuRD) 染色质重塑复合物合作，通过调节转录输出来决定肾单位祖细胞的命运该应用程序将测试 Wnt/ß-连环蛋白。该模型结合遗传、基因组和生化方法进行了关键预测。在目标 1 中，我们将确定 Sall1 是否直接上调帽间充质中的 Six2 表达以抑制祖细胞的分化。 Wnt9b（主要分化信号）的表达在 Sall1 突变体中增加。确定增加的 Wnt9b 和减少的 Six2 表达的组合是否足以导致加速肾单位形成，以及自我更新祖细胞的耗竭，目标 2 将确定 Sall1 和 NuRD 如何控制肾单位祖细胞中的转录输出，以确定是否未承诺的前体细胞。细胞进行自我更新或启动肾单位分化，从这些研究中获得的机制见解将推动肾单位祖细胞的体外和/或增殖的努力。促进成熟肾小管上皮细胞的再生，以纠正肾单位缺陷。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Sall1-NuRD interaction regulates multipotent nephron progenitors and is required for loop of Henle formation.

Sall1-NuRD 相互作用调节多能肾单位祖细胞，并且是 Henle 环形成所必需的。

DOI：
发表时间：
2017-09-01
期刊：
影响因子：
0
作者：
Basta, Jeannine M;Robbins, Lynn;Denner, Darcy R;Kolar, Grant R;Rauchman, Michael
通讯作者：
Rauchman, Michael

Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.

截短的 SALL1 阻碍汤斯-布罗克斯综合征的初级纤毛功能。

DOI：
发表时间：
2018
期刊：
影响因子：
9.8
作者：
Bozal;Martín;Pirone, Lucia;Liang, Yinwen;Sigurðsson, Jón Otti;Gonzalez;Giordano, Immacolata;Gabicagogeascoa, Estibaliz;de Luca, Angela;Rodríguez, Jose A;Wilkie, Andrew O M;Kohlhase, Jürgen;Eastwoo
通讯作者：
Eastwoo

The core SWI/SNF catalytic subunit Brg1 regulates nephron progenitor cell proliferation and differentiation.

核心 SWI/SNF 催化亚基 Brg1 调节肾单位祖细胞增殖和分化。