title: The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo.
abstract: Podocytes are specialized kidney cells that form the kidney filtration barrier through the connection of their foot processes. Nephrin and Neph family transmembrane molecules at the surface of podocytes interconnect to form a unique type of cell-cell junction, the slit diaphragm, which acts as a molecular sieve. The cytoplasmic tails of Nephrin and Neph mediate cytoskeletal rearrangement that contributes to the maintenance of the filtration barrier. Nephrin and Neph1 orthologs are essential to regulate cell-cell adhesion and Rac-dependent actin rearrangement during Drosophila myoblast fusion. We hypothesized here that molecules regulating myoblast fusion in Drosophila could contribute to signaling downstream of Nephrin and Neph1 in podocytes. We found that Nephrin engagement promoted recruitment of the Rac exchange factor Dock1 to the membrane. Furthermore, Nephrin overexpression led to lamellipodia formation that could be blocked by inhibiting Rac1 activity. We generated in vivo mouse models to investigate whether Dock1 and Dock5 contribute to the formation and maintenance of the kidney filtration barrier. Our results indicate that while Dock1 and Dock5 are expressed in podocytes, their functions are not essential for the development of the glomerular filtration barrier. Furthermore, mice lacking Dock1 were not protected from LPS-induced podocyte effacement. Our data suggest that Dock1 and Dock5 are not the important exchange factors regulating Rac activity during the establishment and maintenance of the glomerular barrier.
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM); Montréal, QC, Canada; Département de Médecine (Programmes de Biologie Moléculaire); Université de Montréal; Montréal, QC, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Laurin
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM); Montréal, QC, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Dumouchel
authors.affiliation: Division of Immunogenetics; Department of Immunobiology and Neuroscience; Medical Institute of Bioregulation; Kyushu University; Fukuoda, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM); Montréal, QC, Canada; Département de Médecine (Programmes de Biologie Moléculaire); Université de Montréal; Montréal, QC, Canada; Département de Biochimie; Université de Montréal; Montréal, QC, Canada; Division of Experimental Medicine; McGill University; Montréal, QC, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D004330:Drosophila; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism*; D008070:Lipopolysaccharides; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032446:Myoblasts / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C581047:DOCK1 protein, mouse; C531318:Dock5 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C113267:nephrin; D020744:rac GTP-Binding Proteins
keywords: Dock1; Dock180; Dock5; Elmo; Rac; Rho GTPase; podocyte