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: 7218716
• 负责人: MICHAEL I RAUCHMAN
• 金额: $ 17.18万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218716
• 关键词: Alleles; Animal Model; Biochemical; Cells; Condition; DNA; Defect; Development; Dominant-Negative Mutation; Drosophila genus; Embryo; Embryonic Development; Event; Family member; Gene Targeting; Genes; Genetic; Heterodimerization; Homodimerization; Human; Kidney; Laboratories; Mammals; Mediating; Metanephric structure; Middle Lobe Syndrome; Molecular; Mus; Mutant Strains Mice; Mutation; N-terminal; Organ; Organogenesis; Orthologous Gene; Pathogenesis; Pattern; Phenotype; Proteins; Role; Syndrome; Testing; Transcription Repressor/Corepressor; Type 1 Duane Retraction Syndrome; Work; Zinc Fingers; design; gene function; gene repression; mouse model; mutant; nephrogenesis; protein function; research study; transcription factor

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（由申请人提供）：本申请的长期目标是了解控制脊椎动物肾脏发育中离散步骤的分子事件。Sall 1是一个进化上保守的多锌指转录因子，尽管其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，SIII 1 -4。SALL 1突变导致常染色体显性遗传先天性异常综合征，Townes-Brocks（TBS），其特征在于多器官缺陷，包括肾脏囊性发育不全。小鼠同种异体Sall 1缺陷导致肾发育不全，表明Sall 1对后肾发育至关重要。果蝇中Sall 1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节胚胎发育、细胞命运和终末分化。虽然这些研究确立了萨尔基因在胚胎发育中的关键作用，特别是Sall 1在肾脏中的作用，但Sall 1功能的分子机制尚未得到很好的理解。我们的初步研究表明，设计用于模拟TBS突变的小鼠突变体产生截短的N-末端蛋白（SalI 1-N）并重现TBS表型，强烈表明TBS不是由于先前假设的SALL 1单倍不足。这些研究进一步表明，SalI 1-N介导的转录抑制和所有萨尔蛋白之间的相互作用，提示TBS的发病机制的潜在机制。本研究旨在探讨TBS的发病机制及Sall 1在肾脏发育中的作用。在具体目标1中，我们将研究截短的Sall 1蛋白导致Townes-Brocks综合征发育缺陷的机制。具体目标2将检查Sall 1在后肾发育早期事件中的作用，并确定其与其他萨尔基因的关系。具体目标3将寻求识别下游靶基因并定义Sall 1的DNA识别序列。这些实验将为Sall 1蛋白的功能提供重要的新信息， 我们对脊椎动物肾脏发育的分子控制和TBS的发病机制的理解。这一建议也有更广泛的意义，了解萨尔基因功能的器官发生一般和冲广综合征的发病机制，一个遗传性的条件，结果从类似的截短突变SALL 4。