title: Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells.
abstract: During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta-gonad-mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. Using a combination of ex vivo and in vivo approaches, we report here that stage-specific reciprocal dorso-ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. Our study strongly suggests that these inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways. Specifically, Shh produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP inhibitory signals in the ventral tissue are integral parts of the regulatory system involved in the development of HSCs.
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Céline
authors.initials: C
authors.lastname: Souilhol
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Christèle
authors.initials: C
authors.lastname: Gonneau
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Javier G
authors.initials: JG
authors.lastname: Lendinez
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Antoniana
authors.initials: A
authors.lastname: Batsivari
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Rybtsov
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Wilson
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morgado-Palacin
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: David
authors.initials: D
authors.lastname: Hills
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3052 Melbourne, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3052 Melbourne, Australia.|Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3052 Melbourne, Australia.
authors.forename: Samir
authors.initials: S
authors.lastname: Taoudi
authors.affiliation: STEMCELL Technologies Inc., Vancouver, British Columbia V5Z 1B3, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Antonchuk
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Suling
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, SCRM Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Medvinsky
mesh_terms: D000818:Animals; D001011:Aorta / Q000196:embryology / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006066:Gonads / Q000196:embryology / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008650:Mesonephros / Q000196:embryology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D053823:Hedgehog Proteins; C465570:Shh protein, mouse