Biochemical and Functional Studies of Sall1 in Kidney Development and TBS

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Organogenesis requires the precise temporal and spatial control of gene expression to direct developmental programs that regulate a variety of cellular processes. Sall genes encode for multi-zinc finger transcription factors that are critical conserved regulators of organ development. Mutations in SALL1 cause the Townes-Brocks syndrome (TBS), an autosomal dominant disorder with developmental defects affecting multiple organs. Anomalies of the kidney are prominent in this condition. We created a mouse model of TBS and showed that this syndrome results from dominant effects of a Sall1N truncated mutant protein. These mice display renal hypoplasia with reduced branching of the ureter, similar to that seen in TBS patients. In Sall1 homozygous mutant mice the ureter fails to properly initiate branching resulting in renal agenesis. While these studies indicate that Sall1 is essential for kidney development, the molecular and developmental mechanisms of its function are not well understood. To delineate the function of Sall1 in the kidney it is important to identify Sall1 target genes and determine how these downstream pathways regulate branching morphogenesis of the ureteric bud, maintenance of metaneprhic progenitors and nephron formation. We discovered a novel repression motif in Sall1 (SRM) that is necessary and sufficient to recruit the nucleosome remodeling and deacetylase (NuRD) complex to mediate repression of native Sall1 target genes. Our current model is that regulation of an important subset of Sall1 target genes in developing kidney depends on NuRD recruitment. Based on our preliminary data it is likely that Sall1 acts at multiple steps during nephrogenesis. However, the early arrest of metanephric development exhibited by existing Sall1 alleles has limited investigation of these processes. Since Sall1 is expressed in both the cap mesenchyme (metanephric progenitors) and stromal cells, defining its function in these distinct cellular compartments and at different developmental stages is an important question in the field. These ideas will be tested in three specific aims: (1) Identification and functional analysis of direct Sall1 target genes in metanephric mesenchyme (2) Investigate the role of Sall1 in cap mesenchyme and stromal cells in developing kidney, and (3) Determine the composition of Sall1 native protein complexes in embryonic kidney. These aims will increase our understanding of Sall1 function in nephrogenesis and the etiology of TBS. PUBLIC HEALTH RELEVANCE: Congenital anomalies affecting the kidney and urinary tract are among the most common serious birth defects. While there is significant clinical and increasing genetic data on these disorders, the disease mechanisms are not well understood. The proposed studies will elucidate the molecular pathogenesis of these inherited organ defects and this in turn may lead to novel therapeutic approaches.