title: Interaction of retinoic acid and scl controls primitive blood development.
abstract: Hematopoietic development during embryogenesis involves the interaction of extrinsic signaling pathways coupled to an intrinsic cell fate that is regulated by cell-specific transcription factors. Retinoic acid (RA) has been linked to stem cell self-renewal in adults and also participates in yolk sac blood island formation. Here, we demonstrate that RA decreases gata1 expression and blocks primitive hematopoiesis in zebrafish (Danio rerio) embryos, while increasing expression of the vascular marker, fli1. Treatment with an inhibitor of RA biosynthesis or a retinoic acid receptor antagonist increases gata1(+) erythroid progenitors in the posterior mesoderm of wild-type embryos and anemic cdx4(-/-) mutants, indicating a link between the cdx-hox signaling pathway and RA. Overexpression of scl, a DNA binding protein necessary for hematopoietic development, rescues the block of hematopoiesis induced by RA. We show that these effects of RA and RA pathway inhibitors are conserved during primitive hematopoiesis in murine yolk sac explant cultures and embryonic stem cell assays. Taken together, these data indicate that RA inhibits the commitment of mesodermal cells to hematopoietic fates, functioning downstream of cdx4 and upstream of scl. Our studies establish a new connection between RA and scl during development that may participate in stem cell self-renewal and hematopoietic differentiation.
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Jill L O
authors.initials: JL
authors.lastname: de Jong
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Davidson
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Palis
authors.forename: Praise
authors.initials: P
authors.lastname: Opara
authors.forename: Emily
authors.initials: E
authors.lastname: Pugach
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D004625:Embryo, Nonmammalian; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D017403:In Situ Hybridization; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050982:GATA1 Transcription Factor; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014212:Tretinoin; D029961:Zebrafish Proteins; C494691:gata1a protein, zebrafish; C489367:tal1 protein, zebrafish
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