WASP and the Wiskott Aldrich Syndrome

In mammals, most is known about the loss of function of the haematopoietic WAS gene. In addition to the intense research on the inherited Wiskott-Aldrich syndrome (WAS), two independent WASP knockout mice have been reported (Snapper et al. 1998; Zhang et al. 1999), displaying a mild haematopoietic phenotype reminiscent of less severe WAS in humans (Burns et al. 2004). In 1996, 2 years after the discovery of WASP as the gene mutated in this disease (Derry et al. 1994), two groups independently established the direct interaction of this protein with the Rho family GTPase Cdc42 (Aspenstrom et al. 1996; Symons et al. 1996), raising the possibility of WASP acting in the translation of Cdc42 signalling to actin cytoskeletal reorganisation. The subsequent recognition of the Arp2/3-activating features of WASP/Scar family members (Machesky and Insall 1998; Machesky et al. 1999; Rohatgi et al. 1999) provided the direct connection to actin filament assembly. Hence, a potential Cdc42 ^ WASP/N-WASP ^ Arp2/3 pathway appeared firmly established and provided a first clue on how Cdc42 could induce actin assembly. The most striking cytoskeletal phenotypes in WAS patients and WASP knockout mice are impaired T cell activation upon T cell/antigen-presenting cell (APC) conjugation (Gallego et al. 1997), the lack of surface microvilli on T lymphocytes (Kenney et al. 1986) (although this was questioned recently (Majstoravich et al. 2004)), as well as the failure of haematopoietic cells to form podosomes or to efficiently migrate in vitro (Jones et al. 2002). Indeed, both WASP and N-WASP localise to podosomes and appear essential for their formation (Mizutani et al. 2002).

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