Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule development.
The Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including maintenance of shape, polarity, proliferation, migration, differentiation and morphogenesis. Although previous studies have shown that Cdc42 is required for proper epithelial development and maintenance, its exact molecular function in kidney development is not well understood. In this study, we define the specific role of Cdc42 during murine kidney epithelial tubulogenesis by deleting it selectively at the initiation of ureteric bud or metanephric mesenchyme development. Deletion in either lineage results in abnormal tubulogenesis, with profound defects in polarity, lumen formation and the actin cytoskeleton. Ultimately, these defects lead to renal failure. Additionally, in vitro analysis of Cdc42-null collecting duct cells shows that Cdc42 controls these processes by regulating the polarity Par complex (Par3-Par6-aPKC-Cdc42) and the cytoskeletal proteins N-Wasp and ezrin. Thus, we conclude that the principal role of Cdc42 in ureteric bud and metanephric mesenchyme development is to regulate epithelial cell polarity and the actin cytoskeleton.
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bertha C
BC
Elias
Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Amrita
A
Das
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Diptiben V
DV
Parekh
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Glenda
G
Mernaugh
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Rebecca
R
Adams
Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Zhufeng
Z
Yang
Biotech Research Center, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen DK-2200, Denmark.
Cord
C
Brakebusch
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Veterans Affairs Hospital, Nashville, TN 37232, USA.
Ambra
A
Pozzi
Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Denise K
DK
Marciano
Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Thomas J
TJ
Carroll
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA roy.zent@vanderbilt.edu.
Roy
R
Zent
D000818:Animals; D016764:Cell Polarity / Q000502:physiology*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D007684:Kidney Tubules / Q000196:embryology*; D051379:Mice; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C581598:Cdc42 protein, mouse; D020764:cdc42 GTP-Binding Protein
Epithelial cell; GTPase; Metanephric mesenchyme; Signaling; Ureteric bud