H-Ras, R-Ras, and TC21 differentially regulate ureteric bud cell branching morphogenesis.
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.
Department of Research Medicine, Veterans Affairs Hospital, Nashville, TN 37232, USA.
Ambra
A
Pozzi
Sergio
S
Coffa
Nada
N
Bulus
Wenqin
W
Zhu
Dong
D
Chen
Xiwu
X
Chen
Glenda
G
Mernaugh
Yan
Y
Su
Songmin
S
Cai
Amar
A
Singh
Marcela
M
Brissova
Roy
R
Zent
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D004848:Epithelium / Q000196:embryology / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000737:chemistry / Q000196:embryology* / Q000201:enzymology; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000201:enzymology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009024:Morphogenesis; D015398:Signal Transduction; D014513:Ureter / Q000737:chemistry / Q000196:embryology* / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018631:ras Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D008565:Membrane Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C490200:Rras2 protein, mouse; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins