Glomerular disease is the third most common primary diagnosis of end stage renal disease (ESRD);moreover, greater than 50% of all ESRD patients will secondarily develop glomerular disease. These two patient groups account for a significant portion of the 21.4 billion dollars annually spent on the treatment of ESRD. Malfunction and impaired development of the podocyte are the major mechanisms by which glomerular disease develops. To clarify the mechanisms of podocyte malfunction, it is important to understand the mechanisms of podocyte development. Previously, podocyte development has been studied using single-gene knockout mouse models, which have shown that Forkhead box c2 (Foxc2), LIM homeodomain transcription factor 1(3 (Lmxlb), Musculo-aponeurotic fibrosarcoma oncogene family protein B (MafB), Transcription factor 21 (Tcf21), and Wilms Tumor 1 gene (WT-1) are the necessary transcriptional regulators of podocyte development. It is unclear, however, whether these five transcription factors can explain all aspects of podocyte development. In this proposal, we develop a transcriptional network for podocyte development. We hypothesize that WT-1 is a master gene that initiates the transcriptional network for podocyte development. Using the Xenopus pronephros, we will investigate the transcriptional regulation of podocyte development with a systematic knockdown of podocyte transcription factors to determine their functions. These data will be compiled into a gene regulatory network for podocyte development and quantified using quantitative PCR. Preliminary data are evidence that WT-1 initiates the podocyte transcriptional program and that the program is later controlled by downstream genes MafB and Lmxlb. In a transcriptional network, the initiator must be tightly controlled to prevent overactivation of the pathway. We hypothesize that MafB and Lmxlb perform this function in the podocyte network and thereby regulate podocyte maturation and formation of the slit diaphragm. Preliminary data are indicative of a MafB-regulated negative feedback on WT-1. To characterize this interaction, we will utilize a cross-species approach to understand how expression of WT-1 is regulated. By characterizing the mechanisms of podocyte development in two model systems, we will identify those evolutionary conserved genetic programs that must be perturbed for glomerular disease to develop. This information may be used to develop new biomarkers for diagnosis of glomerular disease and targets for novel therapies. By understanding the genetic basis of cellular development in the glomerulus, we hope to provide new genetic targets to improve the diagnosis and treatment of glomerular diseases.
| White, Jeffrey T; Zhang, Bo; Cerqueira, Debora M et al. (2010) Notch signaling, wt1 and foxc2 are key regulators of the podocyte gene regulatory network in Xenopus. Development 137:1863-73 |
