title: Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1.
abstract: Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs.
authors.affiliation: 1] Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia [2].
authors.forename: Phong Dang
authors.initials: PD
authors.lastname: Nguyen
authors.affiliation: 1] The Kinghorn Cancer Centre &Cancer Research Program, Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia [3].
authors.forename: Georgina Elizabeth
authors.initials: GE
authors.lastname: Hollway
authors.affiliation: Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sonntag
authors.affiliation: Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Lee Barry
authors.initials: LB
authors.lastname: Miles
authors.affiliation: Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Thomas Edward
authors.initials: TE
authors.lastname: Hall
authors.affiliation: Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Silke
authors.initials: S
authors.lastname: Berger
authors.affiliation: The Kinghorn Cancer Centre &Cancer Research Program, Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Kristine Joy
authors.initials: KJ
authors.lastname: Fernandez
authors.affiliation: Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: David Baruch
authors.initials: DB
authors.lastname: Gurevich
authors.affiliation: 1] Anatomy Department, University of Sydney Medical School Anderson Stuart Building University of Sydney, Camperdown, New South Wales 2006, Australia [2] MND Research Program, Australian School of Advanced Medicine, Macquarie University, New South Wales 2109, Australia.
authors.forename: Nicholas James
authors.initials: NJ
authors.lastname: Cole
authors.affiliation: 1] Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia [2] Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton Victoria 3800, Australia.
authors.forename: Sara
authors.initials: S
authors.lastname: Alaei
authors.affiliation: Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Mirana
authors.initials: M
authors.lastname: Ramialison
authors.affiliation: 1] The Kinghorn Cancer Centre &Cancer Research Program, Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia [3].
authors.forename: Robert Lyndsay
authors.initials: RL
authors.lastname: Sutherland
authors.affiliation: 1] Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia [2] Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton Victoria 3800, Australia.
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Polo
authors.affiliation: Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Graham John
authors.initials: GJ
authors.lastname: Lieschke
authors.affiliation: 1] Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia [2] EMBL Australia, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia [3].
authors.forename: Peter David
authors.initials: PD
authors.lastname: Currie
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000196:embryology; D015415:Biomarkers / Q000032:analysis; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000032:analysis / Q000378:metabolism; D002642:Chick Embryo; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019170:Somites / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000032:analysis / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D054377:Chemokine CXCL12; D018398:Homeodomain Proteins; C484871:Meox1 protein, mouse; C000591480:Meox1 protein, zebrafish; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins