Kirmizitas A , Meiklejohn S , Ciau-Uitz A , Stephenson R , Patient R .

MC_UU_12009/8 Medical Research Council , Wellcome Trust , MC_UU_00016/8 Medical Research Council , PG/09/082/28020 British Heart Foundation , PG/14/39/30865 British Heart Foundation , MC_U137981013 Medical Research Council

             hematopoietic stem cell differentiation

	Fig. 1. Expression analysis of BMP ligands and receptors from midgastrulation stage to hemogenic endothelium formation and the description of reagents to inhibit all BMP signaling in blood ontogeny. Primarily, expression in tissues involved in blood stem cell lineage is described. (A) Ligands: bmp2, bmp4, and bmp7 are the principal BMP ligands expressed during gastrulation and onward. At stage 10.5, midgastrulation, bmp2 is expressed in the dorsal mesendoderm. At stage 16, early neurula, bmp2 expression is localized to anterior ventral mesoderm, which encompasses cardiac progenitors and anterior hemangioblasts (AHB). At stage 20–23, bmp2 is expressed along the ventral mesoderm and in lateral plate mesoderm, with signal tapering toward the DLP mesoderm. At stage 26, bmp2 expression is localized along the DLP as well as ventral and cardiac mesoderm. At stages 34–39, bmp2 is expressed in the DA. At stage 10.5, bmp4 is expressed in mesendoderm, with expression diminishing toward dorsal mesendoderm. At stage 16–20, bmp4 is expressed extensively in ventral and lateral mesoderm. From stage 20 onward, bmp4 expression is localized to DLP, encompassing future hemangioblast. At stages 21–26, bmp4 expression is strong along the ventral and lateral plate mesoderm, specifically delineating the DLP tissue at the dorsal most expression domain. At stage 34, bmp4 is expressed in the DA. Bmp5 is not expressed in tissues related to blood lineages, except at stage 38–39, when it is expressed in the DA. Bmp6 is not expressed in HSC lineage. The only expression detectable is transiently in kidney tubules at stage 36. Bmp7 expression at stage 10.5 is localized to ventral most mesendoderm as well as a subset of dorsal mesendoderm. At stages 16–26, bmp7 is expressed along the ventral and lateral plate mesoderm, bordering the kidney field in the dorsal most extent. Bmp7 is strongly expressed in the lateral plate mesoderm for the rest of the developmental stages analyzed. From stage 34 onward, bmp7 is also expressed in the DA. Bmp8 is not expressed during Xenopus development. Bmp9 and bmp10 are expressed in the heart from stage 26 onward. Type I receptors: alk1 is not expressed in early time points; later alk1 expression is primarily restricted to the heart and at stage 38–39 to DA. Alk2 and alk3 are ubiquitously expressed at all stages analyzed. From stage 34 onward, their expression is also observed in the DA. Alk6 is not expressed in blood stem cell lineage but is widely expressed early in dorsal mesoderm and later in neural tissues, neural crest, somites, and notochord. Embryos at stages 10.5 and 34–39 are cleared to enable visualization of the staining of the deeper tissues. For stage 10.5 embryos, D is dorsal and V is for ventral side. For stages 16–20, embryos are visualized from anterior-dorsal (A-D) and anterior-ventral (A-V) angles, except stage 16 bmp4 staining, which is documented from anterior–posterior (A-P) lateral view. From stage 21 onward, the pictures of embryos are taken from lateral view, with anterior–posterior labeled, where it is relevant, on the figure. Expression profile was not determined (nd) for some stages. (Scale bars: 0.5 mm.) (B) BMP2 and BMP4 signal through type I receptors, Alk3 and Alk6. Noggin inhibits signaling by preventing ligands from binding to receptors. DMH1 blocks signaling downstream of Alk3 but not Alk6. (C) BMP5, -6, and -7 signal through type I receptors Alk2, Alk3, and Alk6. Noggin blocks binding of BMP5 and -7 to type I receptors. Noggin does not inhibit signaling downstream of BMP6. DMH1 inhibits Alk2 and Alk3 but not Alk6. (D) BMP9 and -10 signal through type I receptors Alk1 and Alk2. Noggin does not block BMP9 or -10 from binding to receptors. DMH1 blocks Alk1 and Alk2 receptor activity.
	Fig. S1. BMP type II receptors. Type II receptors complement type I receptors and can potentially interact with any type I receptor with ligands being the determinant of the nature of heterocomplexes. Bmpr2 is not expressed at gastrulation, but its expression is activated in the ventral mesoderm from stage 16, later extending to almost all tissues. At stages 34–39, Bmpr2 is also expressed in the DA. Acvr2a is expressed ubiquitously at all stages analyzed. Acvr2b is expressed ubiquitously at gastrulation but later display a restricted expression pattern, being expressed predominantly in neurons. Acvr2b is localized to DA at stage 39. Embryos at stages 10.5 and 34–39 are cleared to enable visualization of the staining in deeper tissues. For stage 10.5 embryos, D indicates dorsal and V indicates the ventral side. For stages 16–20, embryos are visualized from dorsal (D) and ventral (V) angles, with anterior (A) at the top, except stage 16 bmp4 staining, which is documented from an anterior–posterior (A-P) lateral view. From stage 21 onward, the pictures of embryos are taken from a lateral view, with anterior-posterior labeled where it is relevant, on the figure.
	Fig. 2. BMP signaling is required for definitive and primitive hematopoiesis in Xenopus laevis. (A) Noggin protein induced by heat-shock treatment at stage 14 leads to a complete loss of tal1 and hba3 expression in ventral blood islands (arrows) in HS:Noggin transgenic Xenopus stage 32 embryos. Similarly, DMH1 treatment starting from stage 14 blocks tal1 and hba3 expression. (B) Inhibition of BMP signaling by DMH1 from stage 14 abrogates expression of myeloid blood markers mpo and spib at stage 33 compared with DMSO-treated control. (C and D) Inhibition of BMP signaling from stage 14 by Noggin (C) or DMH1 (D) results in the loss of expression of hemogenic endothelium markers runx1, spib, and gfi1a in the DA (red arrow for absence of in treated, green arrows for normal expression in control embryos). (E and F) The endothelium marker pecam1 and arterial gene dll4 is expressed in control as well as treated samples, albeit slightly lower in HS:Noggin embryos. The arterial marker efnb2 is severely reduced in either HS:Noggin-expressing or DMH1-treated embryos (red arrows in E and F). The stages at which the in situ hybridization was performed are indicated on the top left corner. Embryos were photographed from a lateral view, with anterior on the left and dorsal at the top. Numbers in bottom right corner indicate proportion of embryos displaying the phenotype. (Scale bars: 0.5 mm.)
	Fig. S2. Inhibition of BMP signaling by use of HS:Noggin transgenic line and chemical inhibitor DMH1 blocks embryonic myelopoiesis, erythropoiesis, and vasculogenesis. (A) Diagram showing the transgene in HS:Noggin transgenic line. A 15-min heat shock induces myc-noggin protein expression within 30 min. Noggin levels remain steady for at least 24 h after treatment. (B) In situ hybridization on sections of stage 33 embryos shows that induced noggin is expressed across the section in HS:Noggin transgenic siblings. Embryos were heat-shocked for 15 min at 35 °C at stage 32 and fixed 2 h after the heat shock treatment. (C) Inhibition of BMP signaling in heat-shocked noggin (HS:N) and DMH1-treated embryos compared to heat-shocked wild type siblings (wt) or DMSO solvent-treated controls (C) is verified by the loss of P-Smad1/5/8 signal in Western blotting. Embryos were treated from stage14, and DLPs were explanted at stage 25, about 24 h after heat shock, further confirming that noggin protein is active a day after heat shock. Smad1 staining and actin staining were used as loading controls. (D) Timing of BMP requirement in ventral blood island. Inhibition of BMP signaling by DMH1 from stage 12 leads to a strong reduction in primitive myeloid cells originating from both first (mpo, spib) and second (ventral spib staining, red arrow) waves of myelopoiesis. DMH1 treatment blocks hematopoiesis as well as endothelial development when administered from stage 12, at the end of gastrulation. Expression of erythropoiesis markers hba3 and tal1 is absent, and expression of myelopoiesis markers spib and mpo is severely reduced. Endothelial gene expression of aplnr and tek in vitelline vessels, neighboring the ventral blood island, is also absent (red arrows). Aplnr and tek are expressed in the head and the cardinal vein precursors but at a lower level. DMH1 treatment from stage14, early neurulation, eliminates erythroid gene expression, as in treatment starting from stage 12. Spib expression in the periphery of ventral blood island are also absent (red arrow) whereas patrolling myeloid cells, marked by spib and mpo, are unaffected. DMH1 treatment from stage 14 does not block aplnr expression. In 12 of 20 embryos, aplnr expression was expanded to the most ventral tissues in the territory of blood island (blue arrow). DMH1 treatment from stage 14 reduces tek expression (23 of 23 embryos), but in 7 of 23 embryos tek expression was also observed in ventral blood island (blue arrow). (E) DMH1 treatment from stage 12 blocks myeloid gene expression of mpo, spib, and runx1 in anterior hemangioblast/aVBI at stage 16. (F) qRT-PCR analysis of dissected stage 16 aVBI tissue treated with DMH1 from stage 12 shows expression of blood genes gata2, tal1/scl, runx1, and mpo are reduced in stage 16 aVBI tissue, whereas fli1 expression is normal.
	Fig. 3. BMP is required for the specification of hemogenic endothelium before stage 28. (A) Runx1 WISH of heat-shock time course. Runx1 expression is abolished in HS:Noggin siblings when BMP signaling is inhibited before stage 28 (blue box). Arrows mark runx1 expression along the DA, with green arrows indicating normal expression levels and red arrows indicating absent or decreased expression. Expression of runx1 is unaffected when the treatment is started at stage 28 or afterward. Runx1 is also expressed in lateral line nerves (*) as well as in some motor neurons (*), the staining of which in some images is overlaid with runx1 staining in the DA due to embryo positioning and focus. (B) Efnb2 expression is strongly reduced in HS:Noggin siblings when BMP signaling is blocked before stage 28. (C) Dll4 expression is relatively normal in HS:Noggin siblings. However, the DA is not properly lumenized (*) when BMP signaling is inhibited before stage 28. Embryos were visualized from the lateral view, zoomed in to the trunk region, with anterior to the left and dorsal at the top. Proportion of embryos which the image represents is shown in bottom right corner. (Scale bars: 0.5 mm.)
	Fig. S3. BMP is required before stage 28 for the specification hemogenic endothelium. (A) Runx1 WISH of heat-shock time course. Embryos were heat-shocked for 30 min at 35 °C at the stage indicated and were heat-shocked every 24 h until stage 39, when the embryos were collected for analysis. Runx1-expressing cells were then stained by WISH. Embryos are shown from the lateral view, with anterior to the left and dorsal to the top. Green arrows mark the position of the DA, stained for runx1 in control siblings as well as HS:Noggin embryos treated from stage 30. Red arrow shows that runx1 staining in the DA is missing when embryos are heat-shocked starting from stage 20 and 26. HS:Noggin embryos were sorted by visual inspection of shuffled fin and protruding proctodaeum phenotype (blue arrow). Proportion of embryos for which that image represents is shown in bottom right corner. (B) BMP signaling is not required for dll4 expression. Dll4 WISH of heat-shock time course. Embryos were treated as in A and stained for Dll4. The arterial marker dll4 is expressed at all stages analyzed albeit disorganized. (C) Runx1 WISH of DMH1 treatment time course. Embryos were cultured in 0.1× MBS containing 100 μM DMH1 from the stage indicated and were cultured to stage 39, when the embryos were collected for analysis. Runx1-expressing cells were then stained by WISH. Embryos are shown from the lateral view, zoomed into the trunk region, with anterior to the left and dorsal to the top. Green arrows mark the position of the DA, stained for runx1 in control siblings as well as stage 28 DMH1-treated embryos. The red arrow shows that runx1 staining in the DA is missing when embryos are treated starting from stage 24 and decreased when treated starting from stage 26. The blue box highlights stage 28; after that time point, there is no effect on runx1 expression. (D and E) BMP is not required for runx1 maintenance in Xenopus DA. BMP was inhibited from stage 28 by either 100 μM DMH1 treatment or by noggin heat-shock induction. Embryos were collected at stage 43. D, Top shows runx1-expressing cells stained by WISH on wax sections. Sections are 10-μm transversal slices taken through the trunk of the embryo. D, Middle shows embryos, visualized from the ventral aspect, with anterior to the left. The green arrow indicates normal intestinal morphogenesis, which is absent in Bmp-inhibited embryos. D, Bottom shows stage 43 embryo tails, shown from the lateral view, with anterior to the left and dorsal at the top. Bmp-inhibited embryos have an irregular tail fin, whereas control embryos have a smooth edge to the tail fin. Proportion of embryos for which that image represents is shown in bottom right corner in all figures. Images and numbers are from one experiment and are representative of at least three biological replicates except in sectioned embryos. (F) DMH1 inhibits Smad1/5/8 phosphorylation from stage 32 to, and from stage 32–39 without affecting Smad2 phosphorylation level. Treatment with TGFB inhibitors SB505124 and SB431542 from stage 32–39 reduces Smad2 phosphorylation (WB with Millipore anti-Psmad2 Ab no. 04-953) without affecting phospho Smad1/5/8 levels. Smad1 is expressed relatively uniformly between matched DMSO and chemical inhibitor treatments.
	Fig. 4. BMP signaling is required for gata2 expression in the DLP transcriptional network. (A) Hematopoietic programming in the DLP, at stage 25, following heat shock-induced noggin expression at stage 15. Embryos were heat-shocked for 15 min at 35 °C at stage 15 and were collected for analysis at stage 25. Fli1 expression is unaffected in the DLP (green arrows), whereas gata2, kdr, tal1, and lmo2 expression is absent in the DLP as well as ventral blood island (VBI) (red arrows) of HS:Noggin transgenic siblings. Etv2 expression is decreased in the DLP and is absent in VBIs (red arrow). Numbers on individual images show the proportion of embryos for which that image represents (bottom right). (B) qPCR analysis of hemangioblast genes in stage 25 DLPs dissected from control and heat-shock noggin transgenic embryos. Fli1 is not significantly affected, whereas all of the other genes quantified show significant decreases of expression. (C) Hematopoietic programming in the DLP, at stage 26, following heat shock-induced noggin expression at stage 20. The expression of fli1, gata2, etv2, and lmo2 is unaffected. The expression of kdr and tal1 is reduced in the DLP hemangioblasts. HS:Noggin transgenic siblings were identified by the expression of Noggin transcripts (uniform Fast Red staining in HS:Noggin embryos). (D) Gata2 expression in the DA, at stage 36, following heat shock-induced noggin misexpression at stages 23 and 28. Gata2 expression is absent in the DA of HS:Noggin transgenic siblings when heat shock is done at stage 23 (red arrow), whereas gata2 is expressed in the DA of HS:Noggin siblings when heat shock is done at stage 28, compared with wild-type siblings (green arrows). The stage of the embryos are indicated in the top left corner of the top left image. Numbers on individual images shows the proportion of embryos that the image represents (Bottom Right). Images and numbers are from one experiment and are representative of two biological replicates. (Scale bars: 0.5 mm.)
	Fig. S4. Bmp signaling is required for gata2 expression in the DLP. (A) GRN summarizing the known requirements for the programming of DH in the DLP. The timing and tissue of expression is shown by the position of the gene name with gene inputs shown as arrows. Note that arrows do not necessarily signify direct interactions but indicate requirements for expression. Where two gene products physically interact for the expression of a target, their arrows converge on chevrons for receptor ligand interaction or a circle for interactions between transcription factors. Where a gene is shown twice indicates a change in its regulation (gata2 is initiated by fli1 but later requires etv2 for its maintenance). (B) Hematopoietic programming in the DLP, at stage 26, following DMH1 treatment from stage 14. Embryos were treated with 100 μM DMH1 from stage 14 and were collected for analysis at stage 26. WISH was used to stain cells expressing genes that are essential for hematopoietic programming in the DLP: fli1, gata2, kdr, etv2, tal1, lmo2, and hex. Embryos are shown in lateral view, with anterior to the left and dorsal at the top. Red arrowheads mark staining in the DLP. (C) Hematopoietic programming in the DLP at stage 22, following heat shock-induced noggin expression at stage 14. The expression of fli1 in the DLP is unchanged, whereas etv2 is expressed at reduced levels and gata2 and kdr are absent (red arrowheads). Embryos were heat-shocked for 15 min at 35 °C at stage 14 and were collected for analysis at stage 22. WISH was used to stain cells expressing genes that are essential to hematopoietic programming in the DLP: fli1, gata2, kdr, and etv2. (D) Hematopoietic programming in the DLP at stage 22, following DMH1 treatment from stage 14. The expression of fli1 in the DLP is unchanged, whereas etv2 is expressed at reduced levels and gata2 and kdr are absent. Embryos were treated with 100 μM DMH1 from stage 14 and were collected for analysis at stage 22. WISH was used to stain cells expressing genes that are essential for hematopoietic programming in the DLP: fli1, gata2, kdr, and etv2. Embryos are shown in lateral view, with anterior to the left and dorsal at the top. Numbers on individual images show the proportion of embryos that the image represents (Bottom Right). Images and numbers are from one experiment and are representative of two biological replicates.
	Fig. S5. BMP signaling is not required for GRN of the DH after stage 23. Hematopoietic programming in the DLP, at stage 26, following heat shock-induced noggin expression at stage 23. The expression of hemangioblast genes are unaffected in the DLP. The expression of hhex gene is absent in the liver primordium (red arrow) in HS:Noggin siblings compared with wild-type siblings (green arrow). Embryos were heat-shocked for 15 min at 35 °C at the stage 23 and were collected for analysis at stage 26. WISH was used to stain cells expressing genes that are essential for hematopoietic programming in the DLP; fli1, gata2, kdr, etv2, tal1, and lmo2 together with noggin transgene transcripts. HS:Noggin transgenic siblings were identified by the expression of Noggin transcripts (Uniform Fast Red staining in HS:Noggin embryos).
	Fig. 5. Summary of signaling events and downstream transcription factors driving specification of the blood stem cell lineage. The hemangioblast GRN commences with the expression of fli1, which is genetically upstream of gata2 and flk1/kdr (9). Meanwhile, TGFB signaling has an inhibitory effect on fli1 expression (44). BMP signaling, presumably through activation Smad transcription factors, together with Fli1, is first required for gata2 expression before stage 20 (*1) and then for kdr expression at stage 20 (*2) (current study). The genes that are affected consequentially at those stages are colored gray. VEGFA small isoform (VEGFA122) then activates Kdr receptor which lead to the expression of scl/tal1 and hhex (14). Finally, BMP signaling is still required at stage 23–26 for the initiation of gata2 expression later in the DA (*3) (current study). Later, VEGFA medium isoform (VEGFA170) from somites induces Notch1, which in turn is required for the maintenance of gata2 expression and induction of runx1 (14). The requirements for each signaling pathway are indicated by color-matching the text with the transcription factors. The three inputs from BMP signaling are shown with asterisks (*).

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