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 events1-3. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 314-318 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 512 |
| Issue number | 7514 |
| DOIs | |
| Publication status | Published - 21 Aug 2014 |
Bibliographical note
Funding Information:Acknowledgements We thank G. Kardon and B. Hogan for reading and critique of the manuscript. We also thank C.-H. Wang, F. Ellett, V. Nikolova-Krstevski and Fishcore staff for technical assistance. This work was supported by a National Health and Medical Research Council of Australia (NHMRC) grant to P.D.C. and an Australian Research Council grant to P.D.C. and G.E.H.; G.E.H. was supported by a Cancer Institute NSW (CINSW) Career Development Fellowship, R.L.S. by the CINSW and RT Hall Foundation, P.D.N. by an Australian Postgraduate Award, G.J.L. by a NHMRC Senior Research Fellowship and P.D.C. by a NHMRC Principal Research Fellowship. The Australian Regenerative Medicine Institute is supported by funds from the State Government of Victoria and the Australian Federal Government.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
Funding
Acknowledgements We thank G. Kardon and B. Hogan for reading and critique of the manuscript. We also thank C.-H. Wang, F. Ellett, V. Nikolova-Krstevski and Fishcore staff for technical assistance. This work was supported by a National Health and Medical Research Council of Australia (NHMRC) grant to P.D.C. and an Australian Research Council grant to P.D.C. and G.E.H.; G.E.H. was supported by a Cancer Institute NSW (CINSW) Career Development Fellowship, R.L.S. by the CINSW and RT Hall Foundation, P.D.N. by an Australian Postgraduate Award, G.J.L. by a NHMRC Senior Research Fellowship and P.D.C. by a NHMRC Principal Research Fellowship. The Australian Regenerative Medicine Institute is supported by funds from the State Government of Victoria and the Australian Federal Government.
ASJC Scopus subject areas
- General