Modelling human Wiskott-Aldrich syndrome protein mutants in zebrafish larvae using live in vivo imaging

Jones, R.A., Feng, Y., Worth, A.J., Thrasher, A.J., Burns, S.O., and Martin, P.
Journal of Cell Science   126(Pt 18): 4077-84 (Journal)
Registered Authors
Feng, Yi, Jones, Rebecca Amy, Martin, Paul
Live imaging, Disease model, WASP, Zebrafish, Immune deficiency, Neutrophils, Macrophages
MeSH Terms
  • Animals
  • Disease Models, Animal
  • Humans
  • Macrophages/metabolism*
  • Neutropenia/congenital*
  • Neutropenia/genetics
  • Neutropenia/metabolism
  • Wiskott-Aldrich Syndrome/genetics*
  • Wiskott-Aldrich Syndrome/metabolism
  • Zebrafish
23868979 Full text @ J. Cell Sci.

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.

Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes