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Vol. 17, Issue 4, 2046-2056, April 2006

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

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

^* Department of Research Medicine, Veterans Affairs Hospital, Nashville, TN 37232; Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; Division of Endocrinology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232; and ^|| Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232

Submitted August 25, 2005; Revised January 3, 2006; Accepted January 26, 2006
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, whereas H-Ras is only detected at day E17.5. Using 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, whereas H-Ras–expressing cells migrated the most and formed long unbranched tubules. These differences in branching morphogenesis are mediated by differential regulation/activation of the Rho family of GTPases and mitogen-activated protein kinases. Because 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, whereas 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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