Sall1 in Kidney Development and Townes-Brocks Syndrome

Sall1 在肾脏发育和汤斯-布罗克斯综合征中的作用

• 批准号: 6882644
• 负责人: MICHAEL I RAUCHMAN
• 金额: $ 18.12万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882644
• 关键词: SDS polyacrylamide gel electrophoresis; cell line; clinical research; congenital kidney disorder; developmental genetics; gene interaction; gene mutation; genetic disorder; genetically modified animals; human genetic material tag; in situ hybridization; intermolecular interaction; laboratory mouse; mammalian embryology; nephrogenesis; nucleic acid sequence; pathologic process; polymerase chain reaction; protein structure function; syndrome; transcription factor; western blottings

DESCRIPTION (provided by applicant): The Long-term objective of this application is to understand the molecular events that control discrete steps in vertebrate kidney development. Sall1 is an evolutionarily conserved multi-zinc finger transcription factor, although its DNA recognition sequence has not been defined. In mammals there are four highly homologous family members, SllI1-4. Mutations in SALL1 result in an autosomal dominant congenital anomaly syndrome, Townes-Brocks (TBS) that is characterized by multi-organ defects including cystic hypoplasia of the kidney. Homoygous deficiency of Sall1 in mice causes renal agenesis indicating that Sall1 is essential for metanephric development. Genetic studies of Sall1 orthologs, spalt (sal), in Drosophila suggest a role for these genes as transcriptional repressors that regulate embryonic patterning, cell fate and terminal differentiation. While these studies establish a critical role for Sall genes in embryonic development, and in particular for Sall1 in the kidney, the molecular mechanism of Sall1 function is not well understood. Our preliminary studies have shown that a mouse mutant designed to mimic TBS mutations produces a truncated N-terminal protein (SalI1-N) and recapitualtes the TBS phenotypes, strongly suggesting that TBS is not due to SALL1 haploinsufficiency as previously postulated. These studies further demonstrate that SalI1-N mediates transcriptional repression and interaction between all Sall proteins, suggesting potential mechanisms for the pathogenesis of TBS. This proposal will investigate the pathogenesis of TBS and the function of Sall1 in kidney development. In Specific Aim 1 we will investigate the mechanism by which the truncated Sall1 protein leads to developmental defects in the Townes-Brocks syndrome. Specific Aim 2 will examine the role of Sall1 in early events in metanephric development and define its relationship to other Sall genes. Specific Aim 3 will seek to identify downstream target genes and define a DNA recognition sequence for Sall1. These experiments will provide important new information on Sall1 protein function, and advance our understanding of the molecular control of vertebrate kidney development and the pathogenesis of TBS. This proposal also has broader implications for the understanding of Sall gene function in organogenesis in general and for the pathogenesis of Okihiro syndrome, a heritable condition that results from similar truncating mutations in SALL4.

描述(申请人提供)：本申请的长期目标是了解控制脊椎动物肾脏发育的离散步骤的分子事件。SALL1是一个进化上保守的多锌指转录因子，但其DNA识别序列尚未确定。在哺乳动物中，有四个高度同源的家族成员，S11I1-4。SALL1基因突变导致常染色体显性遗传性先天性异常综合征，Townes-Brocks(TBS)，其特征是多器官缺陷，包括肾脏囊性发育不良。小鼠SALL1基因同源缺失可导致肾脏发育不全，提示SALL1在后肾发育中起重要作用。对果蝇SALL1同源基因Spalt(Sal)的遗传学研究表明，这些基因作为转录抑制因子调控胚胎模式、细胞命运和末端分化。虽然这些研究确定了SAL基因在胚胎发育中的关键作用，特别是SALL1在肾脏中的作用，但SALL1功能的分子机制尚不清楚。我们的初步研究表明，旨在模拟TBS突变的小鼠突变体产生一个截短的N-末端蛋白(SalI1-N)并重写TBS表型，这有力地表明TBS并不是由于SALL1单倍体不足所致。这些研究进一步证明，SalI1-N介导了转录抑制和所有SAL蛋白之间的相互作用，提示了TBS发病的潜在机制。本研究拟探讨TBS的发病机制及SALL1在肾脏发育中的作用。在特定目标1中，我们将研究截短的SALL1蛋白导致Townes-Brocks综合征发育缺陷的机制。具体目标2将研究SALL1在后肾发育早期事件中的作用，并确定其与其他SAL基因的关系。特殊目标3将寻求识别下游靶基因，并定义SALL1的DNA识别序列。这些实验将为SALL1蛋白的功能提供重要的新信息，并取得新的进展 我们对脊椎动物肾脏发育的分子调控和TBS发病机制的认识。这一建议也对了解SAL基因在器官发生中的功能以及Okihiro综合征的发病机制具有更广泛的意义，Okihiro综合征是一种由SALL4类似的截断突变引起的遗传性疾病。