Sall1 in Kidney Development and Townes-Brocks Syndrome

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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.