Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae

Abstract

PTPN6 encodes SHP1, a protein tyrosine phosphatase that has an essential role in immune cell function. SHP1 missense and splice site mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in mice that lack functional SHP1 partially. Complete lack of SHP1 function in mouse motheaten mutants leads to severe defects and lethality at 2-6 weeks after birth. Here, we investigated the function of Shp1 in developing zebrafish embryos. We generated a ptpn6 knockout zebrafish line lacking functional Shp1. Zebrafish develop ex utero and are transparent, which facilitates analysis of the function of Shp1 during early hematopoietic development. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). During early development the myeloid lineage was affected, which resulted in a decrease in the number of neutrophils, and a concomitant increase in the number of macrophages. The number of emerging hematopoietic stem and progenitor cells (HSPCs) was decreased, but due to hyperproliferation, the number of HSPCs was higher in ptpn6 mutants than in siblings at 5 dpf. Finally, directional migration of neutrophils and macrophages was decreased in response to wounding and less macrophages were recruited to the wound site. Yet, regeneration of the caudal fin fold was normal. We conclude that loss of Shp1 impairs neutrophil and macrophage function and caused severe inflammation and lethality at the larval stage.