Associate Professor of Internal Medicine
Associate Professor of Biochemistry & Molecular Biology
Nephrology Section Chief, St. Louis VA Medical Center

EDUCATION:
M.D.C.M., 1984, McGill University Faculty of Medicine

MEMBERSHIPS:
American Society of Nephrology
American College of Physicians
Society for Developmental Biology
American Society of Biochemistry & Molecular Biology

HONORS:
Fellow Royal College of Physicians & Surgeons of Canada
American Heart Association Established Investigator Award

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Congenital anomalies of the urinary tract are among the most common serious birth defects. Impaired outgrowth and branching of the ureteric bud is a common developmental mechanism that leads to renal hypoplasia (small kidneys) or agenesis (no kidneys form). Our lab focuses on understanding the molecular genetic basis of mammalian kidney development and on how disruption of specific pathways leads to abnormal development of this vital organ. We use the mouse as our model system.


The role of Sall genes in kidney development
Mutations in the gene encoding for the zinc finger transcription factor SALL1 result in kidney and other organ defects that define the autosomal dominant syndrome Townes-Brocks (TBS). Our lab has created a faithful mouse model of this syndrome and demonstrated that expression of a truncated mutant Sall1 protein is responsible for these developmental defects. Currently we are using genetic approaches in the mouse, including Cre recombinase-mediated tissue specific gene inactivation, to define the role of Sall1 in kidney development and elucidate the pathogenesis of TBS. Genome wide screens using transcriptional profiling and chromatin immunoprecipitation (ChIP) are underway to define Sall1 target genes in the kidney.

Mutations in SALL4 cause Okihiro syndrome, another autosomal dominant disorder associated with multiple organ defects. Sall4 appears to have a role in kidney development that is distinct from Sall1. We are using Sall4 mouse mutants and reporter mice that express GFP in the developing kidney to uncover the function of Sall4 in proper outgrowth and branching of the ureter.

We discovered a novel 12 amino acid repression motif in Sall proteins (SRM) that recruits the nucleosome remodeling and deacetylase (NuRD) complex to regulate target gene expression. Sall1 target genes identified in our unbiased genome wide screens are being tested for NuRD dependent regulation using ChIP and RNAi mediated knock down of NuRD specific components in embryonic kidney cell lines.

Renal epithelial cell regeneration after acute kidney injury (AKI)
The kidney has the capacity to recover from acute ischemic and toxic insults by regenerating tubular epithelia. Reutilization of developmental pathways is thought to play a key role in this process. We are using ischemia reperfusion injury in adult mice to define the role of Sall1 and other developmental regulators in tissue regeneration in the kidney. AKI is a common condition associated with poor outcomes in patients. Our long term goal is to understand how the repair process is regulated so that new therapeutic strategies can be developed.

Figure 1. Kidney defects in Sall mouse mutants
Whole mount view of embryonic day 11.5 mouse developing kidneys carrying the Hoxb7-GFP transgene to visualize the branching ureteric bud. In the Sall1 TBS mouse mutant the ureteric bud grows out from the nephric duct but does not initiate branching, resulting in renal agenesis (left panel). In Sall4 mutants there is a duplication of the ureter (right panel). In wild type mice (middle) the ureteric bud grows out and properly initiates the first branching event (T stage).


Figure 2. Branching morphogenesis in the kidney
Whole mount view of embryonic day 16 kidney showing extensive branching of the ureter. Branching events take place reiteratively to induce the ~10,000 individual filtering units (nephrons) in the mouse kidney.