title: A somitic Wnt16/Notch pathway specifies haematopoietic stem cells.
abstract: Haematopoietic stem cells (HSCs) are a self-renewing population of cells that continuously replenish all blood and immune cells during the lifetime of an individual. HSCs are used clinically to treat a wide array of diseases, including acute leukaemias and congenital blood disorders, but obtaining suitable numbers of cells and finding immune-compatible donors remain serious problems. These difficulties have led to an interest in the conversion of embryonic stem cells or induced pluripotent stem cells into HSCs, which is not possible using current methodologies. To accomplish this goal, it is critical to understand the native mechanisms involved in the specification of HSCs during embryonic development. Here we demonstrate in zebrafish that Wnt16 controls a novel genetic regulatory network required for HSC specification. Non-canonical signalling by Wnt16 is required for somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), and these ligands are, in turn, required for the establishment of definitive haematopoiesis. Notch signalling downstream of Dlc and Dld is earlier than, and distinct from, known cell-autonomous requirements for Notch, strongly suggesting that novel Notch-dependent relay signal(s) induce the first HSCs in parallel to other established pathways. Our results demonstrate that somite-specific gene expression is required for the production of haemogenic endothelium.
authors.affiliation: Department of Cellular and Molecular Medicine and Section of Cell and Developmental Biology, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0380, USA.
authors.forename: Wilson K
authors.initials: WK
authors.lastname: Clements
authors.forename: Albert D
authors.initials: AD
authors.lastname: Kim
authors.forename: Karen G
authors.initials: KG
authors.lastname: Ong
authors.forename: John C
authors.initials: JC
authors.lastname: Moore
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Lawson
authors.forename: David
authors.initials: D
authors.lastname: Traver
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D019170:Somites / Q000166:cytology / Q000378:metabolism*; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C064045:delta protein; C468126:dld protein, zebrafish; C559646:wnt16 protein, zebrafish