A WHIM-sical zebrafish

Abstract

In this issue of Blood, Walters and colleagues describe an elegant model of WHIM syndrome in the zebrafish embryo. By allowing the movement of WHIM neutrophils to be observed in live animals, this model dramatically illustrates the dynamics of the interaction between the neutrophil chemokine receptor CXCR4 and its receptor ligand (stromal-derived factor-1 [SDF-1], also known as CXCL12) in th hallmark of WHIM-excessive neutrophil adhesion to the marrow stroma.

Wild-type neutrophils in the bone marrow express CXCR4 and interact with stromal cells expressing SDF1. This interaction activates CXCR4 (“on”), sending a blocking signal to the cells' motility apparatus, which prevents egress from the marrow. As the neutrophils mature, CXCR4-SDF1 is internalized and degraded (“off”), which leads to Rac activation, allowing the cells to migrate out of the marrow. WHIM syndrome patients express a dominant gain-of-function C-terminal truncation of CXCR4. Walters and colleagues have shown that CXCR4^WHIM nonetheless requires the binding of SDF-1 to activate CXCR4^WHIM (“on”), blocking motility. CXCR4^WHIM is not internalized, so the “on” signal persists, resulting in retention of neutrophils in the marrow, and ultimately apoptosis. This retention can be bypassed, either by knocking down SDF-1, or activating Rac, the G-protein that drives actin polymerization and neutrophil motility.