Congenital abnormalities of the kidney are the major cause of pediatric kidney disease which encompass renal agenesis, juvenile cystic disease, nephrotic syndromes, and Wilms tumor. Understanding kidney development not only guides our understanding of congenital kidney disease but also provides a framework for developing interventions to restore kidney function. Many known disease genes are transcription factors and signaling molecules that regulate kidney organogenesis;in this proposal we aim to understand how regulatory and signaling molecules function to drive initial formation of the kidney and how they might be harnessed to promote kidney tubule regeneration. We have discovered that the odd- skipped related1 (osr1) gene is required to regulate the development of all nephron cell types in zebrafish and for nephrogenesis in mice. We propose extending our comparative analysis of osr1 function in zebrafish and mouse to characterize a distinct cell-autonomous role for osr1 in podocyte differentiation and a non-cell autonomous role for osr1 in tubule cell and angioblast differentiation. Mosaic analysis of osr1-deficient cells in zebrafish embryos, knockdown approaches in mouse kidney explant culture, and generation of a conditional Osr1 knockdout mouse will be used to further our understanding of conserved functions of osr1 in kidney cell differentiation and nephron patterning. Cell non-autonomous effects of osr1-deficiency in zebrafish appear to be due to altered wnt signaling. We will examine wnt signaling and the function of frizzled receptors in previously unexplored contexts including nephric duct formation, nephron patterning, and recovery from kidney injury. Insights gained from this work will guide future efforts to direct kidney progenitor cell differentiation and restore kidney tubule function after injury.

Public Health Relevance

Birth defects associated with impaired kidney development are the primary cause of pediatric kidney disease and can have long lasting effects into adulthood. Chronic kidney disease that results is currently only treatable by kidney dialysis or transplant. We aim to better understand kidney birth defects and apply what we learn about gene regulation and cell signaling to new approaches to treating pediatric and adult kidney disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Hoshizaki, Deborah K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Terashima, Alexandra V; Mudumana, Sudha P; Drummond, Iain A (2014) Odd skipped related 1 is a negative feedback regulator of nodal-induced endoderm development. Dev Dyn 243:1571-80
Palmyre, Aurélien; Lee, Jeongeun; Ryklin, Gennadiy et al. (2014) Collective epithelial migration drives kidney repair after acute injury. PLoS One 9:e101304
Lam, Pui-Ying; Kamei, Caramai N; Mangos, Steve et al. (2013) odd-skipped related 2 is required for fin chondrogenesis in zebrafish. Dev Dyn 242:1284-92
Sanna-Cherchi, S; Sampogna, R V; Papeta, N et al. (2013) Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med 369:621-9
Drummond, Iain A (2013) The cilium in lights: new views of an ancient organelle. BMC Biol 11:74
Kamei, Caramai N; Kempf, Herve; Yelin, Ronit et al. (2011) Promotion of avian endothelial cell differentiation by GATA transcription factors. Dev Biol 353:29-37
Drummond, Iain A; Davidson, Alan J (2010) Zebrafish kidney development. Methods Cell Biol 100:233-60
Vasilyev, Aleksandr; Liu, Yan; Mudumana, Sudha et al. (2009) Collective cell migration drives morphogenesis of the kidney nephron. PLoS Biol 7:e9
Drummond, Iain A (2008) Some assembly required: renal hypodysplasia and the problem with faulty parts. J Am Soc Nephrol 19:834-6
Mudumana, Sudha P; Hentschel, Dirk; Liu, Yan et al. (2008) odd skipped related1 reveals a novel role for endoderm in regulating kidney versus vascular cell fate. Development 135:3355-67

Showing the most recent 10 out of 11 publications