Ciau-Uitz A , Pinheiro P , Kirmizitas A , Zuo J , Patient R .

Medical Research Council , MC_U137981013 Medical Research Council , MC_UU_12009/8 Medical Research Council , MRC_MC_U137981013 Medical Research Council , MRC_MC_UU_12009/8 Medical Research Council

	Fig. 1. Characterisation of DLP mesoderm adult haemangioblasts. (A) Adult haemangioblasts localise in the DLP adjacent to the somites and are the earliest HSC progenitors detectable by co-expression of VEGFR2, Flk1, and the stem cell leukaemia gene (Scl), which marks the emergence of haemangioblasts. The panel on the right shows co-expression of the endothelial gene, Fli1, and Scl on a 10 μM section. Note that no morphological differences are observed between adult haemangioblasts and surrounding tissues. (B) Expression analysis revealing novel haematopoietic, Lyl1, Sox7 and CBFβ, as well as novel endothelial, Etv2, Elk3, Fli1-like, Egfl7 and Tie2, gene expression in adult haemangioblasts. (C) Adult haemangioblasts do not express the early mesodermal marker, Brachyury (Bra), nor the erythrocyte differentiation genes, Gata1, Globin, biKLF, Gfi1b, Ferrochelatase (Fech), Eto2 and Fog. (D) Adult haemangioblasts do not express genes associated with mature blood vessels, CD31, AA4, Ami, Klf2, Vecad and VWF. (E) Adult haemangioblasts do not express key HSC-associated genes such as Runx1, SpiB, Gfi1a, cMyb and Ikaros (Ika). (F) Expression of CD41, a gene associated with haematopoietic commitment, and CD45, which is associated with haematopoietic differentiation, are undetectable in adult haemangioblasts. The DLP is indicated by the red or black arrows. All embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. All embryos are shown at stage 26. (G) Schematic representation of the location of the DLP adult haemangioblast population and its derivatives. (i) Representation of a stage 26 embryo showing in red the Scl expression domains, the ventral blood island and the DLP mesoderm. (ii) Cross section of a stage 26 embryo, at the level indicated by the line in panel i, showing the location of the DLP. Note that adult haemangioblasts (red tissue) lies immediately ventral to the somites (yellow tissue) but at some distance from the hypochord (green tissue), where the DA and HSCs eventually emerge. (iii) Picture showing DA/HSC progenitors migrating from the DLP to the hypochord, a process taking place from stage 28 to 31. (iv) Schematic representation of HSCs emerging in association with the ventral wall of the DA; these haematopoietic clusters are found from stage 42 to 44, 4 days after the specification of adult haemangioblasts in the DLP. Hyp, hypochord; n, notochord; s, somites; VBI, ventral blood island.
	Fig. 2. Scl marks and is essential for the emergence of adult haemangioblasts in the DLP. (A) Bar chart summarising the haematopoietic (magenta and red) and endothelial (green) expression hierarchy in the DLP reveals that adult haemangioblast programming takes place in four discrete transcriptional steps. Expression profiles were obtained by analysis of embryos subjected to whole-mount in situ hybridisation. Stages of development by morphological traits (NF) and hours post fertilisation (Hpf) are indicated at the top and are as indicated by Nieuwkoop and Faber (Nieuwkoop and Faber, 1967). (B) Expression analysis showing haematopoietic (Scl, Sox7 and Lyl1) and endothelial (Flt1, Flt4, Egr1, Elk3 and Egfl7) genes dependent on Scl for their expression in the DLP (arrows). (C) Expression analysis showing that haemogenic endothelium, as indicated by Runx1 and Gfi1a, fails to be established in the DA of Scl morphants. The DA is indicated by red arrows. (D) Expression analysis showing that the haematopoietic genes, Gata2, Lmo2 and Etv6; and the endothelial genes, Fli1, Flk1, Etv2 and Hex, in the DLP, as well as the expression of the growth factor, VegfA, are not dependent on Scl. The DLP is indicated by the red arrow. All embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. Embryos in B and D were analysed at stage 26, whereas those in C are stage 39 embryos. Numbers of embryos represented by each panel, out of the number analysed, are indicated in the top right corner. n, neurons, VBI, ventral blood island.
	Fig. 3. Fli1 and Gata2 regulate Etv6/VEGFA signalling in the DLP to control the establishment of adult haemangioblasts. (A) Expression analysis showing that the expression of Fli1, Gata2 and Flk1 in the DLP (arrows) are not dependent on Etv6/VegfA signalling. (B) Expression analysis showing that the expression of Etv6, VegfA, Scl and Flk1 in the DLP (arrows) are dependent on both Fli1 and Gata2 transcriptional activities and that Gata2 expression is controlled by Fli1. (C) Expression analysis showing that the expression of Etv6 and VegfA in the DLP (arrows) is dependent on VEGFA signalling. (D) Expression analysis in staged embryos shows that Etv6 controls the expression of VegfA in the DLP (arrows) and in the somites (striped staining) but not in the hypochord (arrowheads). Note that VegfA expression in the somites is initially completely dependent on Etv6 but that by stage 24 some recovery is observed. (E) Diagram summarising the genetic cascade regulating Scl expression in the DLP. Relationships between genes are depicted by an arrow from the regulating gene to the regulated genes. This regulatory network shows that, although Fli1 and Gata2 are required for Etv6, VegfA and Scl expression, the establishment of endogenous VEGFA signalling and Scl expression in the DLP can only happen when VEGFA is produced in the somites, that paracrine VEGFA signalling is absolutely required for the initiation of the adult haemangioblast programme. The open circle indicates the interaction between the VEGFA receptor, Flk1, and VEGFA ligand from the somites. The arrow with chevrons indicates that VEGFA activates Scl indirectly, and that an intermediate factor controlled by VEGFA signalling is required. All embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. All embryos are shown at stage 26, unless otherwise indicated. Numbers of embryos represented by each panel, out of the number analysed, are indicated in the top right corner.
	Fig. 4. Etv2 acts downstream of Fli1 to control Gata2 and adult haemangioblast specification. (A) Expression analysis showing that Etv2 is a major regulator of gene expression in the DLP (arrows). Note that Etv6 and VegfA expression in the DLP is not dependent on Etv2. (B) Analysis of the transcriptional regulation of Etv2 in the DLP. Expression analysis showing that Etv2 expression in the DLP (arrows) is not dependent on Etv6/VEGFA signalling but dependent on Fli1 and Gata2. Note Etv2 ectopic expression in Fli1 morphants (arrowhead). (C) Expression analysis in staged embryos showing that Gata2 expression in the DLP (arrows) is initially independent of Etv2's transcriptional regulation but is controlled by Etv2 after stage 24 of development. All embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. All embryos are shown at stage 26, unless otherwise indicated. Numbers of embryos represented by each panel, out of the number analysed, are indicated in the top right corner. (D) Diagram summarising an endogenous cell-autonomous and VEGFA-independent genetic cascade required for Scl expression in the DLP. This cascade is initiated by Fli1 and maintained by Etv2.
	Fig. S1. Expression of haematopoietic and endothelial genes in DLP adult haemangioblasts. (A) In situ hybridisation showing ETS TFs not expressed in the DLP. Black arrows indicate the position of the DLP. All embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. All embryos are shown at stage 26. (B) In situ hybridisation analysis showing the expression of blood and endothelial genes not expressed in adult haemangioblasts (Fig. 1) but expressed in developing blood vessels or developing blood cells. All embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. All embryos are shown at stage 34. (C) Expression analysis in sectioned control and Etv6 morphants showing co-expression of Lmo2 and VegfA in the DLP. In control embryos, dark blue staining (VegfA) masks the turquoise staining (Lmo2) in the DLP (red arrow) where both transcripts are expressed. By contrast, in Etv6 morphants, VegfA is no longer expressed in the DLP and therefore Lmo2 staining can be visualised (red arrow). Sections are in transverse orientation with dorsal to the top. Sections are taken from stage 26 embryos. DA, dorsal aorta; Hyp, hypochord; Lpm, lateral plate mesoderm; n, notochord; s, somites; Thromb, thrombocytes; VitV, vitelline vessels.
	Fig. S2. SCL is required for embryonic erythrocyte differentiation. (A) Diagram showing the sequence targeted by the antisense MO (red nucleotides) blocking the translation of the two X. laevis SCL alleles. Initiation ATG is in purple. Sequences targeted by Scl MO2 and Scl MO3 are also indicated. (B) Western blot showing depletion of SCL protein in embryos injected with SCL MO at the two-cell stage. 2xHA-SCL, present only in stage 10 sample, indicates HA-tagged protein generated from exogenous mRNA. Note that no endogenous SCL protein is detected at stage 10. ACTIN was used as a loading control. (C) In situ hybridisation analysis showing the absence of embryonic erythrocytes, as indicated by expression of embryonic Globin and Gfi1b (arrows), in SCL morphants. Embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. All embryos are shown at stage 34. Numbers of embryos represented by each panel, out of the number analysed, are indicated in the top right corner.
	Fig. S3. Etv2 is not required for Flk1 expression in adult haemangioblasts. (A) Expression analysis showing that Flk1 expression in Etv2-deficient embryos is normal in adult haemangioblasts (stage 24 and 26, arrows) but absent in post-adult haemangioblast stages, stage 35. (B) Expression analysis showing the absence of differentiated endothelial markers, Erg1 and Tie2, in post-adult haemangioblast Etv2 morphants, indicating a complete lack of blood vessels in these embryos. Embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. Numbers of embryos represented by each panel, out of the number analysed, are indicated in the top right corner.
	Fig. S4. Fli1 and Gata2 are required for Etv2 expression in the DLP. (A) Expression analysis showing that Etv2 expression in the DLP is not initiated in Fli1 morphants. (B) Expression analysis showing that Etv2 expression is not initiated in the DLP of Gata2 morphants. Embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. The DLP is indicated by arrows. The arrowhead in Fli1 MO indicates Etv2 ectopic expression in the somites. Numbers of embryos represented by each panel, out of the number analysed, are indicated in the top right corner.
	Fig. S5. Adult haemangioblast programming in Fli1 morphants is not rescued by exogenous Gata2 mRNA. Fli1 MO was co- injected with a hormone-inducible form of Gata2, Gata2FL-GR-AH, at the two-cell stage and grown to stage 20 when Gata2FL-GR- HA activity was induced with 10 mM dexamethasone (Dex). Embryos were then further cultured and collected at the stages indicated. Expression of Flk1 at stage 22, Etv2 at stage 24 and Scl at stage 26 was not rescued in the DLP (arrows). Nevertheless, Scl expression in developing erythrocytes in the ventral blood island was significantly rescued (red arrowheads). Black arrowheads indicate Etv2 ectopic expression in the somites. Embryos were hybridised as whole mounts and are shown in lateral view, with anterior to the left and dorsal to the top. Numbers of embryos represented by each panel, out of the number analysed, are indicated in the top right corner.
	kdr (kinase insert domain receptor (a type III receptor tyrosine kinase) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	tal1 (T-cell acute lymphocytic leukemia 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	etv2 (ETS variant transcription factor 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	elk3 (ELK3, ETS-domain protein (SRF accessory protein 2)) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	fli1b (Fli-1 proto-oncogene, ETS transcription factor beta) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	eglf7 (EGF-like-domain, multiple 7) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	lyl1 (lymphoblastic leukemia derived sequence 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	sox7 (SRY (sex determining region Y)-box 7) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	cbfb (core-binding factor subunit beta) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. Key: dorsal lateral plate mesoderm is indicated by the red arrow.
	tek (TEK tyrosine kinase, endothelial) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The dorsal lateral plate mesoderm is indicated by the red arrow.
	gfi1b (growth factor independent 1B transcription repressor) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The region of the dorsal lateral plate mesoderm is indicated by the arrow.
	cbfa2t3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	gata1 (GATA binding protein 1 (globin transcription factor 1)) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	klf4 (KLF transcription factor 4) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	fech (ferrochelatase) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	zfpm1 (zinc finger protein, FOG family member 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	pecam1 (platelet/endothelial cell adhesion molecule 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	cfd (complement factor D (adipsin)) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	cdh5 (cadherin 5, type 2, VE-cadherin (vascular epithelium)) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	cd93 (CD93 molecule) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	klf2 (KLF transcription factor 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	vwf (von Willebrand factor) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	runx1 (RUNX family transcription factor 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up. The position of the dorsal lateral plate mesoderm is indicated by the arrow.
	gfi1 (growth factor independent 1 transcription repressor) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	ikzf1 (IKAROS family zinc finger 1 (Ikaros) ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	spib (Spi-B transcription factor (Spi-1/PU.1 related) ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	cmyb ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	itga2b.1 (integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41), gene 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	ptprc (protein tyrosine phosphatase, receptor type, C) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	flt1 (fms-related tyrosine kinase 1) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	flt4 (fms-related tyrosine kinase 4) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	erg (v-ets avian erythroblastosis virus E26 oncogene homolog) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	etv6 (ets variant transcription factor 6) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	vegfa (vascular endothelial growth factor A) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	gata2 (GATA binding protein 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	lmo2 (LIM domain only 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	ets1 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	ets2 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	elf1 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	elf2 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	elf3 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	etv7 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	elk4 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 26, lateral view, anterior left, dorsal up.
	pecam1 ( ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34, lateral view, anterior left, dorsal up.
	cfd (complement factor D (adipsin)) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34, lateral view, anterior left, dorsal up.
	cdh5 (cadherin 5, type 2, VE-cadherin (vascular epithelium)) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34, lateral view, anterior left, dorsal up.
	cd93 (CD93 molecule) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34, lateral view, anterior left, dorsal up.
	klf2 (KLF transcription factor 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34, lateral view, anterior left, dorsal up.
	vwf (von Willebrand factor) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34, lateral view, anterior left, dorsal up.
	Schematic showing, in red, the gene expression domain of tal1 (T-cell acute lymphocytic leukemia 1) the earliest marker for haemangioblasts in the Xenopus tadpole, NF stage 26: dorsal lateral plate mesoderm (DLP) and the ventral blood island (VBI).
	A schematic of NF stage 26 Xenopus tadpole in transverse section, showing position of the the dorsal lateral plate mesoderm (DLP), at the dorsal most aspect of the lateral plate mesdoerm ( LP). Somites (s), notochord n) and the hypocord (Hyp) are also indicated.

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