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MBC in Press, published online ahead of print February 8, 2006
Mol. Biol. Cell 10.1091/mbc.E05-08-0800

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Submitted on August 25, 2005
Revised on January 3, 2006
Accepted on January 26, 2006

H-Ras, R-Ras, and TC21 Differentially Regulate Ureteric Bud Cell Branching Morphogenesis

Ambra Pozzi,*{dagger}{ddagger} Sergio Coffa,{dagger} Nada Bulus,{dagger} Wenqin Zhu,{dagger} Dong Chen,{dagger} Xiwu Chen,{dagger} Glenda Mernaugh,{dagger} Yan Su,{dagger} Songmin Cai,{dagger} Amar Singh,{dagger} Marcela Brissova,*{sect} and Roy Zent*{dagger}{ddagger}||

*Department of Research Medicine, Veterans Affairs Hospital, Nashville, TN 37232; Divisions of {dagger}Nephrology and {sect}Endocrinology, Department of Medicine and Departments of {ddagger}Cancer Biology and ||Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232

Monitoring Editor: Keith Mostov

The collecting system of the kidney, derived from the ureteric bud (UB), undergoes repetitive bifid branching events during early development followed by a phase of tubular growth and elongation. Although members of the Ras GTPase family control cell growth, differentiation, proliferation and migration, their role in development of the collecting system of the kidney is unexplored. In this study we demonstrate that members of the R-Ras family of proteins, R-Ras and TC21, are expressed in the murine collecting system at E13.5, while H-Ras is only detected at day E17.5. Utilizing murine UB cells expressing activated H-Ras, R-Ras and TC21, we demonstrate that R-Ras expressing cells show increased branching morphogenesis and cell growth, TC21 expressing cells branch excessively but lose their ability to migrate, while H-Ras expressing cells migrated the most and form long unbranched tubules. These differences in branching morphogenesis are mediated by differential regulation/activation of the Rho family of GTPases and MAP kinases. As most branching of the UB occurs early in development, it is conceivable that R-Ras and TC-21 play a role in facilitating branching and growth in early UB development, while H-Ras might favor cell migration and elongation of tubules, events that occur later in development.

Address correspondence to: Roy Zent (roy.zent{at}vanderbilt.edu)




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