Interaction of retinoic acid and scl controls primitive blood development.
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.
de Jong
Jill L O
JL
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Davidson
Alan J
AJ
Wang
Yuan
Y
Palis
James
J
Opara
Praise
P
Pugach
Emily
E
Daley
George Q
GQ
Zon
Leonard I
LI
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
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
Mol Endocrinol. 1995 Sep;9(9):1135-46
7491106
Physiol Rev. 2000 Jul;80(3):1021-54
10893430
Development. 1993 Aug;118(4):1255-66
8269852
Dev Biol. 1998 May 15;197(2):248-69
9630750
PLoS Biol. 2007 Nov;5(11):e304
18031199
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16924-9
17068127
Biochem Pharmacol. 1988 Apr 15;37(8):1639-42
3358794
Development. 1996 Dec;123:311-9
9007251
Blood. 1995 Jul 1;86(1):156-63
7795222
PLoS Genet. 2007 Oct;3(10):1922-38
17953490
Dev Biol. 2001 Jan 1;229(1):89-101
11133156
Annu Rev Genet. 2005;39:481-501
16285869
Blood. 2008 May 15;111(10):4944-53
18252864
Blood. 2008 Oct 15;112(8):3194-204
18684862
Nature. 1997 Apr 3;386(6624):488-93
9087406
Oncogene. 2004 Sep 20;23(43):7233-46
15378083
Dev Dyn. 2008 May;237(5):1218-31
18429046
Curr Opin Cell Biol. 2001 Dec;13(6):673-8
11698182
Cell. 1998 Jan 23;92(2):241-51
9458048
Dev Biol. 2004 Jul 1;271(1):119-29
15196955
Dev Biol. 2006 Apr 15;292(2):506-18
16457800
Dev Dyn. 1995 Jul;203(3):253-310
8589427
Development. 1999 Nov;126(22):5073-84
10529424
EMBO J. 1998 Jul 15;17(14):4029-45
9670018
Development. 1997 Aug;124(16):3111-21
9272952
Nat Genet. 1999 Apr;21(4):444-8
10192400
Cell. 2002 Apr 5;109(1):29-37
11955444
Nucl Recept Signal. 2009 May 08;7:e005
19471584
Nat Rev Genet. 2008 Jul;9(7):541-53
18542081
Cell. 2008 Sep 19;134(6):921-31
18805086
Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19081-6
16357205
Curr Biol. 1994 Mar 1;4(3):189-202
7922324
Development. 1996 Dec;123:303-9
9007250
Exp Hematol. 2008 Dec;36(12):1593-603
18809240
Blood. 2009 Mar 12;113(11):2375-85
19056693
Blood. 2009 Jul 2;114(1):60-3
19321862
Development. 2006 Dec;133(23):4709-19
17079270
J Biol Chem. 1996 May 24;271(21):12209-12
8647816
Nature. 2003 Sep 18;425(6955):300-6
13679919
Dev Biol. 2005 Jan 15;277(2):522-36
15617691
Blood. 2002 Apr 1;99(7):2379-86
11895770
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7756-61
18511567