Vav1/2/3-null Mice Define an Essential Role for Vav Family Proteins in Lymphocyte Development and Activation but a Differential Requirement in MAPK Signaling in T and B Cells

Fujikawa, Keiko; Miletic, Ana V.; Alt, Frederick W.; Faccio, Roberta; Brown, Tracie; Hoog, Jeremy; Fredericks, Jessica; Nishi, Shinzo; Mildiner, Shirly; Moores, Sheri L.; Brugge, Joan S.; Rosen, Fred S.; Swat, Wojciech

doi:10.1084/jem.20030874

Cited by 211 publications

(252 citation statements)

References 44 publications

Supporting

Mentioning

234

Contrasting

Order By: Relevance

“…Three Vav proteins share 50-60% amino-acid homology and have been demonstrated to exert both redundant and specific functions in hematopoietic cells as defined by studies of mice lacking these genes (Bustelo, 2000;Fujikawa et al, 2003). Vav1 is the best characterized family member.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

Siefring

Wang

et al. 2006

Oncogene

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

Siefring

Wang

et al. 2006

Oncogene

View full text Add to dashboard Cite

“…Consequently, attention has been focused mainly on the role of vav in lymphocyte development and the immune response (Turner and Billadeau, 2002;Fujikawa et al, 2003). In addition, the three mammalian vav genes are also expressed in some areas of the CNS (Movilla and Bustelo, 1999;Betz et al, 2003;Chauvet et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The Guanine Exchange FactorvavControls Axon Growth and Guidance duringDrosophilaDevelopment

Malartre

Ayaz²,

Amador³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

The Vav proteins are guanine exchange factors (GEFs) that trigger the activation of the Rho GTPases in general and the Rac family in particular. While the role of the mammalian vav genes has been extensively studied in the hematopoietic system and the immune response, there is little information regarding the role of vav outside of these systems. Here, we report that the single Drosophila vav homolog is ubiquitously expressed during development, although it is enriched along the embryonic ventral midline and in the larval eye discs and brain. We have analyzed the role that vav plays during development by generating Drosophila null mutant alleles. Our results indicate that vav is required during embryogenesis to prevent longitudinal axons from crossing the midline. Later on, during larval development, vav is required within the axons to regulate photoreceptor axon targeting to the optic lobe. Finally, we demonstrate that adult vav mutant escapers, which exhibit coordination problems, display axon growth defects in the ellipsoid body, a brain area associated with locomotion control. In addition, we show that vav interacts with other GEFs known to act downstream of guidance receptors. Thus, we propose that vav acts in coordination with other GEFs to regulate axon growth and guidance during development by linking guidance signals to the cytoskeleton via the modulation of Rac activity.

show abstract

“…Rearrangement of the actin cytoskeleton is regulated during both T cell receptor signaling and T cell migration (7)(8)(9), but much less is known about its requirement during T cell development. The small Rho-family GTPases and their guanine nucleotide exchange factors (GEFs), proteins known to regulate the actin cytoskeleton, are clearly required during thymocyte development (10)(11)(12). Although these molecules are also known to regulate cell adhesion and migration, their involvement in thymocyte trafficking has not been thoroughly assessed.…”

mentioning

confidence: 99%

Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development

Cotta-de-Almeida

Westerberg

Maillard

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

120

View full text Add to dashboard Cite

cytoskeleton ͉ thymus ͉ migration ͉ colitis ͉ knockout mice L ymphoid progenitors enter the thymus to initiate a complex differentiation process resulting in maturation of T cells (1, 2). The well characterized maturation steps of ␣␤ T cells in the thymus are also governed by trafficking events and positional cues driven by guidance molecules, including chemokines, adhesion molecules, and extracellular matrix components (3-6). Rearrangement of the actin cytoskeleton is regulated during both T cell receptor signaling and T cell migration (7-9), but much less is known about its requirement during T cell development. The small Rho-family GTPases and their guanine nucleotide exchange factors (GEFs), proteins known to regulate the actin cytoskeleton, are clearly required during thymocyte development (10-12). Although these molecules are also known to regulate cell adhesion and migration, their involvement in thymocyte trafficking has not been thoroughly assessed. The small GTPase effector molecule Wiskott-Aldrich syndrome protein (WASP) has also been demonstrated to be a critical regulator of antigen receptor signaling, actin cytoskeletal rearrangements, and lymphocyte migration (13-22). Although WASP deficiency has been correlated with lower numbers of naïve T cells (23), WASP does not seem to play a critical role in T cell development. Moreover, despite a large body of evidence showing a role for WASP in T cell signaling, its role in thymocyte migration has not been studied. WASP belongs to the WASP family of proteins, including WASP, N-WASP, and WAVE/SCAR molecules 1-3 (24). In particular, N-WASP, which shares 50% homology with WASP, may serve specific and redundant function with WASP in hematopoietic cells. In fact, we have shown that expression of N-WASP in WASP-deficient T cells partly restores CD3-mediated proliferation, implying that WASP and N-WASP might share functions in T cells (25).Here we sought to explore the importance of cytoskeletal regulation for thymocyte development by examining the unique and redundant roles of WASP and N-WASP. Using two complementary approaches, we analyzed T cells devoid of WASP and N-WASP and demonstrated that thymopoiesis cannot proceed in the absence of WASP and N-WASP. Results Deletion of WASP and N-WASP in Lymphocytes Using the RAG-2-Deficient Complementation System Leads to a Block in T Cell Development.We have demonstrated that lymphoid development is normal in WASP knockout (WKO) mice (20). We hypothesized that N-WASP might have some overlapping functions with WASP during lymphopoiesis and sought to investigate the unique and redundant activities for WASP and N-WASP in T cell development and function. To circumvent the embryonic lethality of N-WASP germ-line inactivation in mice (26), we used the RAG2-deficient blastocyst complementation system (27). Blastocysts from RAG-2-deficient mice implanted into foster mothers generate animals that fail to rearrange antigen receptor genes and consequently lack mature B and T cells. Injection of gene-targeted ES cells into RAG-2-...

show abstract

Vav1/2/3-null Mice Define an Essential Role for Vav Family Proteins in Lymphocyte Development and Activation but a Differential Requirement in MAPK Signaling in T and B Cells

Cited by 211 publications

References 44 publications

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

The Guanine Exchange FactorvavControls Axon Growth and Guidance duringDrosophilaDevelopment

Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development

Contact Info

Product

Resources

About