Cdc42 is required for PIP2-induced actin polymerization and early development but not for cell viability

Abstract

Our studies clearly demonstrate that Cdc42 mediates PIP(2)-induced actin assembly, and document a critical and unique role for Cdc42 in this process. Moreover, we conclude that, unexpectedly, Cdc42 is not necessary for viability or proliferation of mammalian early embryonic cells. Cdc42 is, however, absolutely required for early mammalian development.

Gene Targeting of Cdc42 and Cdc42GAP Affirms the Critical Involvement of Cdc42 in Filopodia Induction, Directed Migration, and Proliferation in Primary Mouse Embryonic Fibroblasts

“…Recent studies of Cdc42 function using genetic knockout approach in ES and ES-derived fibroblastoid clones (Chen et al, 2000;Czuchra et al, 2005) raise concerns about the physiological significance of some of previous findings. Our present work demonstrating that Cdc42 is critically involved in actin filopodia formation, cell motility, directional migration, and cell growth and is required for the serum regulation of PAK1, GSK3␤, MLC, ERK1/2, JNK, and NF-B pathways in primary MEFs help affirm that Cdc42 indeed can play these roles in primary cells.…”

“…In Cdc42-deficient ES or ES-derived fibroblastoid cells, cell growth proceeds normally without mitotic defects (Chen et al, 2000;Czuchra et al, 2005). In primary MEFs, however, Cdc42 activity is critical for cell proliferation, as loss or gain of activity of Cdc42 affects cell cycle progression and/or survival ( Figure 7; Wang et al, 2005).…”

“…Surprisingly, direct knockout of Cdc42 gene in embryonic stem (ES) cells does not appear to affect cell proliferative potential or alter the ERK1/2, p38, and JNK MAP kinase signaling that have previously been suggested to be regulated by Cdc42 (Chen et al, 2000). More intriguingly, a recent study using loxP/Cre-mediated deletion of Cdc42 from an ES-derived fibroblastoid cell line indicated that Cdc42 is dispensable for actin filopodia induction, directed migration, cell polarization, and mitosis (Czuchra et al, 2005).…”

“…The current biochemical model depicts that upon activation of a variety of cell surface receptors, Cdc42 can be activated to recognize specific downstream effectors to regulate multiple cell functions including actin cytoskeleton reorganization (Hall, 1998), directional migration, gene expression, and cell cycle S-phase progression (Kjoller and Hall, 1999;Ridley, 2001;Etienne-Manneville and Hall, 2002). Although genetic evidence for the related cell functions of Cdc42 is particularly strong in lower eukaryotes including Saccharomyces cerevisiae and Caenorhabditis elegans (Johnson and Pringle, 1990;Gotta et al, 2001;Kay and Hunter, 2001), genetic support for these roles of Cdc42 in mammalian cells is limited, in part because conventional gene targeting of Cdc42 leads to early embryonic lethality (Chen et al, 2000), and most published literature on mammalian Cdc42 cell function are derived by using dominant negative or constitutively active mutant expression approaches in clonal cell lines.…”

Macrophage Effector Functions Controlled by Bruton’s Tyrosine Kinase Are More Crucial Than the Cytokine Balance of T Cell Responses for Microfilarial Clearance

“…This defect in phagocytosis was also observed in preliminary flow cytometric experiments (data not shown). Defective phagocytosis in Btk-deficient macrophages is interesting in light of the reported connections between Btk, Wiskott-Aldrich syndrome protein, Cdc42, and actin polymerization (37)(38)(39).…”