Sall1 in Kidney Development and Townes-Brocks Syndrome

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离散步骤的分子事件。Sall1是一种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SllI1-4。SALL1基因突变可导致常染色体显性先天性异常综合征towes - broks (TBS)，其特征是包括肾囊性发育不全在内的多器官缺陷。小鼠同源性缺乏Sall1导致肾发育不全，表明Sall1对肾后发育至关重要。对果蝇Sall1同源基因spalt （sal）的遗传研究表明，这些基因作为转录抑制因子调节胚胎模式、细胞命运和终末分化。虽然这些研究确定了Sall1基因在胚胎发育中的关键作用，尤其是肾中的Sall1基因，但Sall1功能的分子机制尚不清楚。我们的初步研究表明，一种模拟TBS突变的小鼠突变体产生了一个截断的n端蛋白（SalI1-N），并重现了TBS表型，这强烈表明TBS并非如先前假设的那样是由于SALL1单倍不全造成的。这些研究进一步表明，SalI1-N介导了所有Sall蛋白之间的转录抑制和相互作用，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在肾脏发育中的功能。在Specific Aim 1中，我们将研究截断的Sall1蛋白导致唐斯-布罗克斯综合征发育缺陷的机制。特异性目标2将检查Sall1在后肾发育早期事件中的作用，并定义其与其他small基因的关系。Specific Aim 3将寻求鉴定下游靶基因并定义Sall1的DNA识别序列。这些实验将为Sall1蛋白功能的研究提供重要的新信息，并进一步推进Sall1蛋白的研究

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.