Dissecting the mechanisms through which Wnt5 signaling influences hematopoiesis

University Of Massachusetts Boston, Dorchester MA

Investigators

Abstract

Project Summary/Abstract: During blood cell differentiation (hematopoiesis), a precise balance must be achieved between hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal, and differentiation. If this balance is not properly achieved, hematological diseases such as leukemia can result. There is mounting evidence that Wnt signaling plays an important role in regulating this balance during normal hematopoietic development, and dysregulation of Wnt signaling is implicated in leukemias and other hematologic diseases. Therefore, it is important to understand how Wnt signaling is regulated during hematopoiesis to achieve a balance between HSPC maintenance and differentiation. Wnt signaling can occur through canonical or non-canonical pathways, and the role of the latter mechanism(s) in hematopoiesis is not well understood. The proposed research program uses the Drosophila melanogaster blood system as a model system to address unresolved questions how non-canonical Wnt5-mediated Wnt signaling affects hematopoiesis. We recently discovered mechanisms by which canonical Wnt signaling and a non-canonical Wnt6-mediated pathway act in specific subsets of HSPCs to control HSPC maintenance, cell division, growth, and differentiation. We also see evidence that Wnt5 signaling plays a role in HSPC maintenance and differentiation during hematopoiesis. This proposal consists of two Aims that will elucidate the molecular mechanisms involved in Wnt5- mediated signaling during hematopoiesis and dissect how Wnt5 signaling integrates with other signaling pathways involved in hematopoietic development such as the canonical Wnt pathway. In Aim 1 we will dissect the signaling pathways downstream of Wnt5 in order to identify the receptors and signaling intermediates required for Wnt5 to exert its effects on hematopoiesis. We will also dissect the relationship between signaling components downstream of Wnt5 and identify potential transcriptional targets of Wnt5 signaling. In Aim 2 we will identify which cells produce and respond to Wnt5 and pinpoint when in development this signaling occurs. Uncovering the molecular mechanisms required for homeostatic control of Wnt signaling during hematopoiesis will provide valuable insights into mechanisms that cause aberrant Wnt signaling in hematological diseases.