Non-canonical Wnt signaling and lymphostromal interactions: the role of Wnt4/Frizzled6 axis in early immune development

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All cells of the adult immune system are derived from a small number of bone marrow hematopoietic stem cells (HSC) that are found in specialized pockets or niches, surrounded by other cells that are believed to regulate HSC function. In addition to being able to develop into the different blood cell lineages, HSC also have the unique ability to self-renew. Their infrequent cell divisions are asymmetrical, resulting in the generation of one daughter HSC, identical to the mother cell, and one progenitor cell that has lost several stem cell characteristics. This self-renewal is dependent on HSC-niche interactions and is essential for the continuous generation of circulating blood cells. One of the greatest technical challenges in the field is to develop methods for HSC expansion in culture while limiting the loss of their self-renewal capacity.I am interested in the regulation of HSC-niche interactions by the Wnt-family of signaling proteins. In particular, my recent results have identified a non-traditional signaling pathway that is involved in the regulation of HSC numbers in mouse bone marrow. One of the molecules involved is the cell surface receptor protein Frizzled6. The pathway is known to regulate cellular orientation and cell-cell interaction in the skin. I propose that the same signals could also be involved in the interaction of HSC with the bone marrow niche cells and control the orientation of HSC inside the niche, thus influencing their self-renewal.The current research proposal focuses on the influence of Frizzled6 on HSC-niche interactions, HSC orientation inside the niche, and the localization of other associated proteins inside the cell. Together the work proposed here will improve our understanding of the mechanisms that regulate HSC localization in the bone marrow. Furthermore, these studies should lead to the identification of novel growth factors for HSC expansion in culture and the development of mouse models to facilitate further research on non-traditional Wnt signaling.