Jones, R.A., Feng, Y., Worth, A.J., Thrasher, A.J., Burns, S.O., and Martin, P. (2013) Modelling human Wiskott-Aldrich syndrome protein mutants in zebrafish larvae using live in vivo imaging. Journal of Cell Science. 126(Pt 18):4077-84.
Wiskott Aldrich syndrome (WAS) and X-linked neutropenia (XLN) are immunodeficiencies in which the functions of several haematopoietic
cell lineages are perturbed due to mutations in the actin regulator WASp. From in vitro cell biology experiments and biochemical and structural approaches we know much about the functional domains of WASp, and
how WASp might regulate the dynamic actin cytoskeleton downstream of activators such as Cdc42, but in vivo experiments are much more challenging. In patients there is a correlation between clinical disease and genotype, with severe
reductions in WASp expression or function associating with complex multilineage immunodeficiency, whereas, specific mutations
that cause constitutive activation of WASp result in congenital neutropenia. Here we take advantage of the genetic tractability
and translucency of zebrafish larvae to first characterise how a null mutant in zfWASp influences the behaviour of neutrophils
and macrophages in response to tissue damage and to clearance of infections. We then use this mutant background to study how
leukocyte lineage-specific transgenic replacement with human WASp variants, (including normal wild type, and point mutations
that either fail to bind Cdc42 or cannot be phosphorylated, and a constitutively active mutant equivalent to that seen in
XLN patients), alter the capacity for generation of neutrophils, and their chemotactic response to wounds, and the phagocytic
clearance capacity of macrophages. This model provides a unique insight into WASp-related immunodeficiency at both a cellular
and whole organism level.