Leung A , Ciau-Uitz A , Pinheiro P , Monteiro R , Zuo J , Vyas P , Patient R , Porcher C .

Medical Research Council , G1000729 Medical Research Council , MC_U137961142 Medical Research Council , MC_UU_12009/8 Medical Research Council , MC_U137981013 Medical Research Council , MC_U137961146 Medical Research Council , PG/09/082/28020 British Heart Foundation , MRC_MC_U137961142 Medical Research Council , MRC_MC_U137961146 Medical Research Council , BHF_PG/09/082/28020 British Heart Foundation , MRC_MC_U137981013 Medical Research Council , MRC_G1000729 Medical Research Council , MRC_MC_UU_12009/8 Medical Research Council

	Figure 1. ETO2 Is Necessary for the Onset of Definitive Hematopoiesis(A) Expression analysis showing no difference in expression of primitive erythroid gene alpha T4 globin at stages 22 and 30 in WT and Eto2 morphant embryos. Blue arrowheads, VBI.(B and C) ETO2 morphants show absence of expression of Runx1, Gfi1, SpiB, and Scl in the DA (red arrows) at stage 39. (B) Whole-mount in situ hybridization, WMISH. White arrowheads indicate the notochord. The black arrow (Scl panel, WT embryo) indicates the posterior cardinal vein (PCV) containing Scl-positive primitive erythrocytes. Staining is absent in the ETO2 morphants because circulation is delayed. (C) In situ hybridization on section (ISHS) for SpiB and the endothelial marker Tie2; note that the DA has formed and is lumenized in Eto2 morphants. NT, neural tube. Numbers in the bottom of the panels denote the number of embryos as shown in the panel out of the total examined. Whole mounts are shown with anterior to the left and dorsal to the top. Sections are in transverse orientation with dorsal to the top. See also Figures S1 and S4.
	Figure 2. ETO2 Is Specifically Required for the Establishment of the Hematopoietic Program in the DA(A) Notch1 is absent in the DA of Eto2-MO and Eto2-MO2 morphants (stages 35/36/39, WMISH, and stage 39 bottom, ISHS; red arrowheads, DA; orange arrowheads, notochord).(B and C) Expression analysis of arterial-affiliated genes EphrinB2, Delta-like4 (Dll4), and Notch4 (B), as well as Gata2 (C) in the presumptive DA (stage 32) and in the DA (stages 34–39) in Eto2 morphants, red arrowheads. White and orange arrowheads: neural tube and notochord, respectively.Numbers in the bottom of the panels denote the number of embryos as shown in the panel out of the total examined. Whole mounts are shown with anterior to the left and dorsal to the top. Sections are in transverse orientation with dorsal to the top. See also Figures S2A and S4.
	Figure 3. The Major Axial Vessels Are Normal and Adult Hemangioblasts Are Specified in ETO2 Morphants(A) The endothelial markers CD31, AA4, and Tie2 are expressed normally in the axial vessels of Eto2 morphants (Eto2-MO and Eto2-MO2), revealing the DA (red arrowhead), the PCV (black arrow), and the trunk vasculature (yellow arrow).(B) Abnormal expression of Flk1 in Eto2 morphant DA at stage 39 (red arrowhead), as a consequence of the absence of Notch1. Blue arrowhead: notochord.(C) Specification of adult hemangioblasts is unaffected in ETO2-deficient embryos. Scl is expressed normally at stages 26 in the DLP, primitive erythroid cells, and neurons in Eto2 morphants (Eto2-MO and Eto2-MO2, green, blue, and orange arrowheads, respectively). Flk1 is also expressed normally in the DLP and trunk endothelium of Eto2 morphants (green and blue arrowheads, respectively).Numbers in the bottom right of the panels denote the number of embryos as shown in the panel out of the total examined. Whole mounts are shown with anterior to the left and dorsal to the top. Sections are in transverse orientation with dorsal to the top.(D) Schematic diagram depicting the succession of events leading to HSC specification and the requirement for ETO2. The earliest defect in Eto2 morphants is the loss of Notch1 expression. Molecular markers analyzed in this study are indicated for each stage of development shown.See also Figures S2B–S2D and S4.
	Figure 4. Eto2 Is Expressed in Precursors of Primitive but Not Definitive Blood(A) Eto2 expression (WMISH) from stage 22 to stage 39. Eto2 is found in somitic tissues (yellow arrowheads), the developing VBI (dark blue arrowheads, up to stage 34), and, from stage 30, the neural tube (white arrowheads). At stage 26, no expression was detected in the DLP, delineated by Lmo2 expression (orange arrowhead). Light blue arrowhead, notochord.(B) Eto2 expression (ISHS) was not seen in the DA (red arrowheads, stages 34–43).Whole mounts are shown with anterior to the left and dorsal to the top. Sections are in transverse orientation with dorsal to the top. See also Figures S3 and S4.
	Figure 5. ETO2 Regulates HSC Development through VEGFA170(A) Vegfa expression is downregulated (top right panel) or absent (bottom right panel) in the somites of stage 27 Eto2 morphants (red arrowheads) but maintained in the hypochord (yellow arrowheads), as revealed by ISHS (transverse sections with dorsal to the top).(B) WMISH staining time course reveals downregulation of Vegfa in Eto2 morphant somites; the staining is markedly lighter in morphant embryos at 8 and 11 hr after addition of the staining substrate (anterior to the left, dorsal to the top).(C) Alternative splicing generates VEGFA isoforms with different biological properties. In X. laevis, there are three known VEGFA isoforms (VEGF122, VEGFA170, and VEGFA190). FLK1, FLT1: binding domains for receptors. The C-terminal domain of isoforms VEGFA170 and VEGFA190 is responsible for association with the extracellular matrix (ECM) and the cell membrane. VEGF122 is the diffusible isoform (Cleaver and Krieg, 1998).(D) Levels of isoform-specific VEGFA transcripts in WT and Eto2 morphant somite-hypochord regions at stage 27 (n = 5) quantitated by qPCR. Error bars denote SEM. ∗p < 0.05.(E) Exogenous Vegfa170 expression rescues the HSC program in Eto2 morphants. Embryos were coinjected with Eto2-MO only or Eto2-MO and 4 ng of mRNAs encoding Vegfa122or Vegfa170 isoforms. Rescue of Runx1 and Gfi1 expression in DA (WMISH, red arrowheads) was observed only with Vegfa170 mRNA. Pos, positive; neg, negative. Whole mounts are shown with anterior to the left; dorsal at the top.See also Figure S5.
	Figure 6. Hypomorphic and Isoform-Specific Knockdowns of Vegfa Phenocopy the Eto2 Morphant Phenotype(A) Hypomorphic VEGFA phenotype. The HSC program was abrogated at stage 39 (loss of Runx1 expression), and the early HSC markers Notch1 and Gata2 were absent at stages 34/35 in VEGFA hypomorphs. DA formation (as revealed by the endothelial marker AA4, at stage 34) is unaffected in VEGFA hypomorphs. Decreased expression of arterial marker Dll4 is observed in the DA of Vegfa hypomorphs at stage 34.(B) Top: structure of Xenopus laevis Vegfa gene. Open boxes, exons; thin lines, introns; not to scale. Red lines show the position of the control MO (MOc) and the MOs targeting the intron6/exon7 (MOi6e7) and exon7/intron7 (MOe7i7) splice junctions. Depicted below are the splicing events giving rise to the three known Vegfa isoforms.(C) Vegfa short, medium, and long mRNA isoforms were detected by PCR from material isolated from stage 27 wild-type (WT) embryos or embryos injected with increasing concentrations of MOi6e7 or control MOc (20, 30, and 40 ng). The ethidium-bromide-stained gel shows knockdown of expression of medium and long mRNA isoforms and increased production of the short isoform in MOi6e7 morphants. Asterisk: the band may represent one of the minor Vegfa isoforms as detected in human and mouse, although this has not been confirmed by sequencing.(D) Vegfa medium and long isoform morphant phenotype (Vegfa-MOi6e7). As for Vegfa hypomorphs (A), expression of Runx1, Notch1, and Gata2 is lost. DA formation is unaffected, as revealed by AA4 expression at stage 34. In contrast to Vegfa hypomorphs, expression of the arterial marker Dll4 appears normal.Red arrowheads, DA; light blue arrowheads, notochord; dark blue arrowheads, neural tube; black arrows, posterior cardinal veins (PCV); yellow arrows, trunk vasculature. Numbers at the bottom of the panels indicate the number of embryos with the given phenotype out of the total number examined. Whole mounts are shown with anterior to the left and dorsal to the top.(E) Schematic diagram detailing the phenotypes of ETO2 morphants, VEGFA hypomorphs, and VEGFA morphants with respect to the definitive HSC program. Molecular markers analyzed in this study are indicated for each stage of development shown.See also Figure S6.
	Figure 7. No Epistasis between ETO2, ETV6, and Hedgehog Signaling(A–C) Expression analysis by WMISH of Etv6, Eto2, Ptc1, Vegfa, and Dll4 in Eto2 (A) and Etv6 (B) morphants as well as in embryos treated with cyclopamine (C). Efficiency of Eto2 and Etv6 morpholinos is controlled by Runx1 staining at stage 39, and that of cyclopamine is controlled by Ptc1 staining. Red arrowheads, DA; orange arrowheads, Etv6 staining in the somites; blue arrowheads, notochord; yellow arrowheads, neural tube; white arrowheads, DLP. Numbers at the bottom of the panels indicate the number of embryos with the given phenotype out of the total number examined. Whole mounts are shown with anterior to the left and dorsal to the top.(D) Uncoupling the requirement for VEGFA isoforms during HSC development in Xenopus. Schematic diagram depicting the requirements for VEGFA isoforms in the succession of events leading to HSC formation. Stages 20–23: ETV6 regulates production of VegfA in the somites, VegfA short isoform is critical for correct programming of the adult hemangioblasts in the DLP (green arrows). Stages 24–26: the adult hemangioblasts (or DA precursors) express both endothelial (Flk1) and hematopoietic (Scl) markers and Vegfa in an autocrine manner. The hypochord secretes VegfA short isoform that guides migration of hemangioblasts to the midline (green arrows). Stages 27–30: ETO2 regulates production of VegfA long/medium isoforms (VegfA M/L) in the somites. These isoforms instruct the hematopoietic program of the DA precursors as they migrate along the somites (red arrowheads). Stages 36–41: the DA has formed and is specified as an artery. Cells in the hemogenic endothelium express NOTCH1; this will trigger expression of the HSC transcriptional program. n, notochord.
	Figure S2. Analysis of arteriogenesis and vasculogenesis in Eto2-MO and Eto2-MO2 injected embryos, related to Figures 2, 3. Expression analysis of the arterial marker Cx37 (A, stage 34), the endothelial genes VE-cadh, Ami, Fli1 and AA4 (B-C, stages 37/34), Flt1 and Flt4 (D, stage 26) in Eto2-MO and Eto2-MO2 morphants. Red arrowhead, DA; black arrow, PCV; yellow arrow, trunk vasculature; green arrowhead, DLP. (C) Uncleared embryos, bracket indicates intersomitic vessels (ISVs) sprouting from the PCV in wild-type embryos; the graphs show the number of ISVs observed in wild-type, Eto2-MO and Eto2-MO2 embryos. Numbers at the bottom of the panels indicate the number of embryos with the given phenotype out of the total number examined. Whole mounts are shown with anterior to the left, dorsal to the top.
	Figure S3. Eto2 is not expressed in the DA - Expression pattern of Eto2-related transcripts during development, related to Figure 4. Figure S3. Related to Figure 4. Eto2 is not expressed in the DA - Expression pattern of Eto2- related transcripts during development (A) Laser Capture Microdissection (LCM) was used to isolate specific tissues from stage 39 embryonic sections; the DA and surrounding mesenchyme (DA mes), the neural tube (NT) and gut. NT tissues were intended as a positive control for amplification of the Eto2 transcripts and the gut as a negative control (as expected from WMISH and ISHS results, Figure 4). Gene expression analysis was carried out for Eto2 and the known HSC markers Scl and Runx1 by Reverse Transcription Real Time PCR. Results were normalised to ODC. Errors bars represent the standard deviation from two independent experiments. Unlike the HSC markers, Eto2 expression in the DA mesenchyme is not significantly different from that observed in gut when compared to the high levels observed in the NT. (B, C) Expression of Eto, Mtgr1, Mtgr1-like1 and Mtgr1-like2 was examined during Xenopus development (B) Expression of Eto is detected in the heart fields (stage 22, yellow arrowhead), in the heart (stage 27, yellow arrowhead), in neural cells (stage 22; neural tube at stages 27, 36, 39, white arrowheads) and in the PCV (stages 36/39, blue arrowhead). There was no expression in the DA at stage 39 (red arrowhead). (C) Expression of Mtgr1, Mtgr1-like1 and Mtgr1-like2 is observed in neural cells (white arrowheads stage 22; neural tube at stages 26 and 35), and in the PCV (initiates anteriorly at stage 26, is established by stage 35; blue arrowheads). Mtgr1-like2 is expressed at low levels in the somites (stage 26, orange arrowhead). ISHS at stage 43 shows no expression of Mtgr1 and Mtgr1-like1 in the DA (red arrowhead) and a faint staining for Mtgr-like2 in the region of the DA and surrounding mesenchyme. However, given the lack of homology in the sequences targeted by the Eto2 MOs, it is highly unlikely that expression of Mtgr-like2 was affected in the knock-down experiments. Whole mounts are shown with anterior to the left and dorsal to the top. Sections are in transverse orientation with dorsal to the top.
	Figure S4. Zebrafish ETO2 is required for HSC emergence, related to Figures 1-4. The zebrafish studies provide an independent confirmation of the phenotype observed in Xenopus. Figure S4, related to Figures 1-4. Zebrafish ETO2 is required for HSC emergence (A-C) As in Xenopus, Eto2 is expressed in the trunk somites (A) but not in the dorsal aorta (DA), as seen in transverse sections along the trunk (B, C), at 24hpf (hours post-fertilisation); s, somites; ICM, intermediate cell mass. (D) To test the function of ETO2 in hematopoietic development, we knocked- down its expression using a morpholino that targets the zebrafish Eto2 (Meier et al. 2006). A dose- dependent loss of the HSC markers runx1 and cmyb (another HSC marker (Murayama et al. 2006)) in the DA (black arrowheads) was observed with increasing amounts of Eto2 MO, at 28hpf. In contrast, expression of the arterial marker notch1b was unaffected. (E) At 28hpf, none of the arterial markers analysed (dll4, dlC, notch3/5; DA, black and white arrowheads (Lawson and Weinstein 2002; Nicoli et al. 2008; Rowlinson and Gering 2010)) was affected in Eto2 morphants, whereas runx1 expression was severely downregulated (red arrowheads). Flk1 expression is grossly normal in Eto2 morphants confirming normal endothelialisation. Therefore, down-regulation of Eto2 in zebrafish embryos leads to non cell-autonomous phenotypic defects that are very similar to those observed in Xenopus Eto2 morphant embryos.
	Figure S5.B Expression of a panel of markers implicated in the development of the DA/HSC progenitors in stage 27 WT and Eto2 morphant embryos, related to Figure 5. (also see S5A) (B) Expression of selected markers was examined in stage 27 WT and Eto2 morphant embryo sections by ISHS. There was no discernible alteration in the expression level or the pattern of these markers in the Eto2 morphants. Hypochord; red arrowheads, Neural tube; yellow arrowheads, Somites; orange arrowheads, Notochord; white arrowheads. Sections are in transverse orientation with dorsal to the top.
	Figure S6.A Vegfa hypomorph embryos and Vegfa-MOi6e7 morphants phenocopy the Eto2 morphants, related to Figure 6. (A) Expression of endothelial (Ami, AA4, Flt4), arterial (Cx37) and hemangioblast (Scl and Flk1) genes was examined in Vegfa hypomorph embryos, by WMISH at the stages indicated. Note that AA4 expression was examined on uncleared embryos.
	Figure S6.B. Vegfa hypomorph embryos and Vegfa-MOi6e7 morphants phenocopy the Eto2 morphants, related to Figure 6. (B) Vegfa medium/long isoform morphants (Vegfa-MOi6e7) recapitulate the Eto2 morphant phenotype in the DA. WMISH analysis of hematopoietic (Gfi1, Gata2) endothelial (Flk1, CD31), arterial (Cx37 and Notch4) and hemangioblast (Scl, Flk1) markers reveals that endothelialisation, arterialisation and hematopoietic specification do take place in the morphant DA (red arrowheads). Note, however, the absence of ISVs (AA4, uncleared embryos, brackets), the weak staining of the PCVs (black arrows) and the limited development of the trunk vasculature (yellow arrows) in the Vegfa-MOi6e7 morphants. Numbers at the bottom of the panels indicate the number of embryos with the given phenotype out of the total number examined. Whole mounts are shown with anterior to the left and dorsal to the top. Red arrowheads, DA; black arrows, PCV; brackets, ISVs; pink arrowheads, DLP; yellow arrowheads, VBI; dark blue arrowheads, Scl expression in the neural tube; green arrowheads, Flk1 expression in the trunk endothelium; light blue arrowheads, notochord; yellow arrows, trunk vasculature. Numbers at the bottom of the panels indicate the number of embryos with the given phenotype out of the total number examined. Whole mounts are shown with anterior to the left and dorsal to the top.
	Figure S5, related to Figure 5. Expression of a panel of markers implicated in the development of the DA/HSC progenitors in stage 27 WT and Eto2 morphant embryos. (A) Schematic diagram detailing the signalling events that are proposed to be involved in the specification of the DA and the HSC program; adapted from (Diez et al. 2007).
	Figure S1, related to Figure 1. Design and testing of the Eto2 morpholinos (MOs) (A) Xenopus laevis has a pseudo-tetraploid genome; genes are therefore present in two �pseudo-allele� forms. Sequence alignment of the beginning of the coding sequence of Eto2 pseudo-alleles A and B and Eto-related genes (top) and of the 5� UTR of Eto2 pseudo-alleles A and B (bottom); the target regions for the �ATG� MO (ETO2-MO) and �5�UTR� MO (ETO2-MO2) are highlighted in yellow and blue respectively. The MOs were designed to have 100% homology to the mRNAs transcribed from both Eto2 pseudo-alleles. The nucleotides in red are conserved between Eto2 and the Eto-related transcripts in the region targeted by Eto2-MO. The Eto-related transcripts (Eto, Mtgr1 and two transcripts with high similarity to Mtgr1, namely Mtgr1-like1 (MGC68858) and Mtgr1-like2 (IMAGE 5156021), accession numbers are in Supplemental Experimental Procedures, section Probes used for in situ hybridisaiton) are not targeted by the Eto2 MOs. For Mtgr1, Mtgr1-like1 and Mtgr1-like2, the sequences targeted by the MOs are sufficiently divergent to avoid unspecific targeting effects. Of note, 5 mismatches are recommended to avoid unspecific targeting effects (Eisen and Smith 2008). Given that only 3 nucleotides differ between the Eto sequence and the sequence recognised by Eto2-MO, the Eto transcripts could potentially be targeted. However, as detailed in Figure S3, they are not expressed in hematopoietic or somitic tissues and are therefore unlikely to have any function in hematopoiesis. The sequences targeted by Eto2-MO2 are too divergent to be aligned; this MO is therefore very unlikely to interfere with translation of any of the Eto-related mRNAs. (B) A GFP-reporter mRNA tethered to the 5� region of ETO2 containing the Eto2-MO target sequence (Eto2:GFP) was used to test the efficacy of the MO in vivo. Embryos co-injected with Eto2-MO and Eto2:GFP mRNA had no visible GFP expression (right panel), as opposed to mRNA alone (middle panel). Eto2-MO is therefore able to bind to its intended target sequence in vivo and to block translation. (C) Expression analysis of the HSC markers Gfi1 and SpiB in Eto2-MO2 injected embryos. Red arrow; DA. Numbers at the bottom of the panels indicate the number of embryos with the given phenotype out of the total number examined. Whole mounts are shown with anterior to the left and dorsal to the top.

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