Myd88 is required for haematopoietic development in Drosophila

Abstract

MYD88 is an adaptor protein that has been characterised to transmit immune signals from activated Toll-like receptor (TLR) or Interleukin-1 (IL-1) receptor to the NF-kB pathway. The Toll pathway was first identified in Drosophila, which led to the subsequent discovery of the analogous Toll-like Receptor (TLR) pathway in mammals. Somatic activating point mutations in MYD88 cause a number of haematological malignancies, which include Activated B Cell-Diffuse Large B Cell Lymphoma (ABC-DLBCL), driven in part through increased NF-kB signalling. Although the role of Toll and TLR pathways in modulating response to infectious disease is well-documented, functions in normal haematopoietic development have not been fully elucidated. Therefore, we employed Drosophila to study the function of the conserved Myd88 orthologue in the development of the haematopoietic compartment - the lymph gland. Surprisingly, given activation of mammalian MYD88 drives lymphoma, we demonstrate that haemocyte-specific Myd88 knockdown drives lymph gland overgrowth. Transcriptome profiling of Myd88-depleted lymph glands revealed dysregulation of major developmental signalling pathways, including activation of Ras/MAPK and Wnt/beta-catenin. Furthermore, our genetic interaction studies demonstrated that overgrowth caused by Myd88 knockdown requires beta-catenin activity. Myd88 is, therefore, an essential inhibitor of haematopoietic compartment growth mediated by beta-catenin. Together, these findings not only reveal new roles for Myd88 signalling in development, but also suggest novel mechanisms for the regulation of beta-catenin in haematopoiesis. Future studies investigating potential roles for MYD88 in the regulation of Wnt pathway in mammalian development, may provide insight into novel mechanisms for Wnt-driven cancer.