Lee H , Seidl C , Sun R , Glinka A , Niehrs C .

             BMP signaling pathway

Xla Wt + bmp4 (Fig. 2 a b)
Xla Wt + bmp4 (Fig. S 4 g h)
Xla Wt + bmp4 + CHX + animal cap explant (Fig. 3 c)
Xla Wt + bmp4 + CHX + animal cap explant (Fig. 3 d e )
Xla Wt + bmp4 + animal cap explant (Fig. 3 c)
Xla Wt + bmp4 + animal cap explant (Fig. 3 d e )
Xla Wt + bmp4 + rspo2 + animal cap explant (Fig. 6 c-e)
Xla Wt + bmp4 MO (Fig. 2 e f)
Xla Wt + bmp4 MO (Fig. 2 e f)
Xla Wt + bmp4 MO (Fig. S 2 a b)
Xla Wt + bmpr1a + rspo2 (Fig. 6 b)
Xla Wt + bmpr1a + rspo2 MO + ventro-lateral marginal zone explant (Fig. 6 f-h)
Xla Wt + bmpr1a + rspo2 MO + ventro-lateral marginal zone explant (Fig. 6 f-h)
Xla Wt + chrd.1 MO (Fig. 5 d e)
Xla Wt + chrd.1 MO (Fig. 5 f g)
Xla Wt + chrd.1 MO (Fig. S 6 c d)
Xla Wt + rspo2 (Fig. S 2 c)
Xla Wt + rspo2 MO (Fig. 5 d e)
Xla Wt + rspo2 MO (Fig. 5 f g)
Xla Wt + rspo2 MO (Fig. 6 i)
Xla Wt + rspo2 MO (Fig. 6 i)
Xla Wt + rspo2 MO (Fig. S 6 a b)
Xla Wt + rspo2 MO (Fig. S 6 c d)
Xla Wt + znrf3 MO (Fig. S 7 d e )
Xtr Wt + bmp4 (Fig. 2 g h)
Xtr Wt + bmp4 (Fig. S 4 c d e f)
Xtr Wt + chrd.1 CRISPR (Fig. 2 g h)
Xtr Wt + chrd.1 CRISPR (Fig. S 2 c d)
Xtr Wt + chrd.1 CRISPR (Fig. S 3 f g)
Xtr Wt + lrp6 MO (Fig. 2 g h)
Xtr Wt + nog CRISPR (Fig. S 3 h i)
Xtr Wt + nog CRISPR (Fig. S 4 e f)
Xtr Wt + nog CRISPR + rspo2 CRISPR (Fig. S 4 a b)
Xtr Wt + nog CRISPR + rspo2 CRISPR (Fig. S 4 e f)
Xtr Wt + rspo2 CRISPR (Fig. 2 g h)
Xtr Wt + rspo2 CRISPR (Fig. S 4 c d e f)
Xtr Wt + rspo2 CRISPR + chrd.1 CRISPR (Fig. 2 g h)
Xtr Wt + rspo2 CRISPR + chrd.1 CRISPR (Fig. S 4 c d)

	Fig. 1: RSPO2 and RSPO3 antagonize BMP4 signaling WNT independently. a, b BRE reporter assay in HEPG2 cells upon siControl (a) or siβ-catenin (b) transfection, with or without overnight BMP4 and RSPO1-4 treatment as indicated. n = 3 biologically independent samples. c, d Western blot analyses of phosphorylated Smad1 (pSmad1) and total Smad1 (tSmad1) in HEPG2 cells stimulated by BMP4, treated with or without increasing amount of RSPO2 (c) or RSPO3 (d) overnight. Cells were starved 3–6 h before the stimulation. Ratio, relative levels of pSmad1 normalized to tSmad1. Representative data from two independent experiments are shown. e qRT-PCR analysis of BMP target ID1 in HEPG2 cells upon BMP4, with or without overnightRSPO2 treatment. n = 3 experimentally independent samples. Data are displayed as means ± SD. **P < 0.01, ***P < 0.001 from two-tailed unpaired t-test. f, g BRE reporter assay in HEPG2 cells upon siLRP5/6 and siLGR4/5 knockdowns, with or without overnight BMP4 and RSPO2 treatment as indicated. n = 3 biologically independent samples. h BRE reporter assay in HEPG2 cells stimulated overnight by BMP4 with or without increasing amount of WNT3A treatment. WNT3A activity was validated in Supplementary Fig. 1b. n = 3 biologically independent samples. i Domain structures of RSPO2 and deletion mutants used in j. sp, signal peptide; FU, furin domain; TSP1, thrombospondin domain 1. j BRE reporter assay in HEPG2 cells stimulated overnight with BMP4, and with or without RSPO2 WT or FU1/2 or TSP1 deletion mutants, respectively. n = 3 biologically independent samples. Data for reporter assays (a, b, f–h, j) are displayed as means ± SD, and show a representative of multiple independent experiments. ns, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 from two-tailed unpaired t-test (a, b, f, g, j) or one-way ANOVA with Dunnett test (h). k, l Western blot analyses of phosphorylated Smad1 (pSmad1) and total Smad1 (tSmad1) in H1581 cells upon siRNA transfection as indicated, with 0 h, 1 h, and 2 h of BMP4 stimulation. Ratio, relative levels of pSmad1 normalized to tSmad1. Representative data from two independent experiments are shown.
	Fig. 2: Rspo2 inhibits BMP4 signaling in Xenopus dorsoventral embryonic patterning. a Microinjection strategy for a–f, and representative phenotypes of Xenopus laevis tadpoles (St. 32) injected with the indicated mRNAs radially at 4-cell stage. Dashed lines, head size. Arrowheads, enlarged ventral structure. b Quantification of embryonic phenotypes shown in a. ‘Ventralized’ represents embryos with both small head and enlarged ventral structure, reminiscent of BMP hyperactivation. ‘CE defect’ refers to embryos with convergent extension (gastrulation) defects, unrelated to BMP signaling. Note that rspo2 mRNA dosage used in a was below those that cause gastrulation defects. n = number of embryos. c, d BMP-(vent2) reporter assays with Xenopus laevis neurulae (St.15) injected with reporter plasmids and the indicated Mo at 4-cell stage. n = biologically independent samples and data are displayed as means ± SD. ns, not significant. *P < 0.1, **P < 0.01, ****P < 0.0001 from two-tailed unpaired t-test. e In situ hybridization of vent1 and sizzled in Xenopus laevis gastrulae (St.11, dorsal to the top, vegetal view) injected as indicated. D, dorsal, V, ventral. Asterisk, abolishment of the expression. Dashed line, dorsal blastopore lip (dbl). Scale bar, 0.5 mm. f Quantification of embryonic phenotypes shown in (e). ‘Expressed’, normal, increased or reappearance of vent1/sizzled expression. ‘Abolished’, complete absence of vent1/sizzled expression. Data are pooled from two independent experiments. n = number of embryos. g Microinjection strategy and representative phenotypes of Xenopus tropicalis tadpole (St.30) Crispants and tadpoles (St.30) injected with bmp4 mRNA or lrp6 Mo. At 1-cell stage, Cas9 protein with guide RNA (gRNA) targeting rspo2 or chd, or both gRNAs were injected animally. Dashed lines, head size. Arrowheads, enlarged ventral structure. h Quantification embryonic phenotypes shown in g. ‘Severe’ showed small head, enlarged ventral tissues and short body axis. ‘Mild’ showed one or two of the defects described above. ‘Normal’ showed no visible differences to the uninjected control. n = number of embryos. ns, not significant. **P < 0.01, ***P < 0.001, ****P < 0.0001 from two-tailed χ2 test comparing normal versus ventralized phenotypes (b), two-tailed χ2 test comparing expressed versus abolished (f), or two-tailed χ2 test comparing normal versus severe and mild defects h.
	Fig. 3: Rspo2 is a negative feedback inhibitor in the BMP4 synexpression group. a In situ hybridization of rspo2 and bmp4 in Xenopus laevis at gastrula (St. 11, dorsal to the top, vegetal view), neurula (St. 15, anterior to the top, dorsal view), and tadpole (St. 32, anterior to the left, lateral view). Dashed lines, dorsal blastopore lip (dbl); anp, anterior neural plate; di, diencephalon; mhb, mid-hindbrain boundary; ov, otic vesicle; a, atria; nt, neural tube; de, dorsal eye; h, heart; pdm, proctodeum. Scale bar, 0.5 mm. b Microinjection and experimental scheme for c–e. 2 or 4 cell stage Xenopus laevis embryos were animally injected with control (ppl) or bmp4 mRNA. The animal cap (AC) explants were dissected from injected embryos at stage 8, and either treated or untreated with cycloheximide (CHX) until control embryos reached stage 10 for qRT-PCR (c) or in situ hybridization (d, e). c qRT-PCR of rspo2, sizzled, and vent1 expression in the AC explants injected and treated as indicated. Data are pooled from three independent experiments with similar results and displayed as means ± SD. ns, not significant, *P < 0.05, **P < 0.01, ****P < 0.0001 from two-tailed unpaired t-test. d In situ hybridization of rspo2 and sizzled in the AC explants injected and treated as indicated. e Quantification of (d). n = number of the AC explants. f Model for Rspo2 function as a negative feedback inhibitor of BMP4 in Xenopus dorsoventral patterning.
	Fig. 4: RSPO2 and RSPO3 interact with BMPR1A via the TSP1 domain. a–c BRE reporter assays in HEPG2 cells transfected with constitutively active (QD) BMPR1A (a), ACVR1 (b), or BMPR1B (c) with or without BMP4 and RSPO1-4 treatment overnight. d Cell surface binding assay in HEK293T cells. (Left) Scheme of the assay. Cells were transfected with BMPR1A or LGR4 DNA, and treated with same amount of RSPO1-4-AP upon DSP crosslinking as indicated. Binding was detected as purple stain on cell surface by chromogenic AP assay. (Right) Images of cells transfected and treated as indicated. Data shows a representative from four independent experiments. For quantification, see Supplementary Fig. 5a. Scale bar, 1 mm. e In vitro binding assay between RSPO1-4, FGF and BMPR1AECD. (Left) Scheme of the assay. RSPOs and FGF recombinant proteins were coated on plate as baits, followed by BMPR1AECD-AP treatment overnight. (Right) Bound BMPR1AECD was detected by chromogenic AP assay. Normalized AP activity with control treatment was set to 1. f Scatchard plot of RSPO2 and BMPR1AECD binding to validate Kd for RSPO2-BMPR1A. g Domain structures of the RSPO1 and RSPO2TSP1 with Strep-HA and flag tags used in h. SP, signal peptide; TSP1, thrombospondin domain 1. h In vitro binding assay for RSPOTSP1 and BMPR1AECD. (Left) Scheme of the assay. HA-harboring RSPO1/2TSP1 were captured to HA antibody coated plate, and BMPR1AECD-AP was treated overnight. (Right) Bound BMPR1A to RSPOTSP1 was detected with absorbance. i Domain structures of the RSPO1, RSPO2, and R1-TSPR2. SP, signal peptide; FU, furin domain; TSP1, thrombospondin domain 1. Dashed box indicates the TSP1 domain swapping. j TOPFlash reporter assay in HEPG2 cells upon WNT3A with or without (i) as indicated. k BRE reporter assay in HEPG2 cells upon BMP4 with or without (i) as indicated. For reporter assays (a–c, j, k), n = 3 biologically independent samples; In vitro binding assays (e, h), n = 3 experimentally independent samples. All data are displayed as mean ± SD. ns, not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 from two-tailed unpaired t-test (a, b, e, h, j, k) or one-way ANOVA test (c).
	Fig. 5: Loss of Rspo2-TSP1 domain activates BMP signaling in Xenopus development. a Scheme for rspo2∆TSP splicing Mo in Xenopus laevis. b TOPFlash assay in Xenopus laevis neurulae (St.15) injected radially at 4-cell stage with reporter plasmids and Mo as indicated. Data are displayed as mean ± SD; ns, not significant, ****P < 0.0001 from two-tailed unpaired t-test. n = 3 biologically independent samples. c BMP-reporter (vent2) assay in Xenopus laevis neurulae (St.15) injected radially at 4-cell stage with reporter plasmids and Mo as indicated. Data are displayed as mean ± SD; ***P < 0.001, ****P < 0.0001 from two-tailed unpaired t-test. n = 3 biologically independent samples. d–g In situ hybridization of BMP4 targets vent1 and sizzled in Xenopus laevis. Embryos were injected radially and equatorially at 4-cell stage as indicated. Gastrulae (St.11) (d) and quantification (e); Tadpoles (St. 32) (f) and quantification (g). Dashed lines, dorsal blastopore lip (dbl) (d) or bf1 expression (e); D, dorsal; V, ventral. For f, left, lateral view; middle, magnified view of head; right, magnified view of ventral side. ‘Increased/Decreased’ represents embryos with significant expansion/reduction of sizzled or vent1 signals toward the dorsal/ventral side of the embryo (e), or with significant increase/decrease of the signal strength (g). ns, not significant. n, number of embryos. Scale bar, 0.5 mm. Scoring of the embryos for quantification was executed with blinding from two individuals. For e, g, **P < 0.01, ***P < 0.001, ****P < 0.0001 from two-tailed χ2 test comparing normal versus increased. Data are pooled from at least two independent experiments.
	Fig. 6: RSPO2 removes cell surface BMPR1A. a Western blot analysis in H1581 cells treated with siControl or siRSPO2 as indicated and transfected with or without BMPR1A-HA DNA. Transferrin receptor (TfR), a loading control. Ratio, relative levels of BMPR1A-HA normalized to TfR. Data shows representative result from 3 independent experiments with similar conclusion. b Western blot analysis of Bmpr1a in Xenopus laevis (St. 15) neurulae injected animally at 2-cell to 4-cell stages as indicated. GFP mRNA was injected as an injection control. Ratio, relative levels of Bmpr1a normalized to GFP. Data shows representative result from 3 independent experiments with similar conclusion. c Scheme for immunofluorescence microscopy (IF) in Xenopus laevis animal cap (AC) explants. Embryos were injected animally at 4-cell stage with bmpr1a-EYFP and memb-RFP mRNA along with bmp4 and rspo2 wild-type or mutant mRNA. AC explants were dissected at St.9 for IF. Membrane (memb)-RFP was used as a control comparing relative change of Bmpr1a-EYFP signal at cell surface. d IF for Bmpr1a (green) and cell membrane (red) in AC explants injected as indicated, with a representative cell (top) and magnification (inset). Scale bar, 20 μm. e Quantification of d. n = the number of areas analyzed and data are displayed as mean ± SD. ns, not significant; ****P < 0.0001 from two-tailed unpaired t-test. f Scheme for IF in Xenopus laevis ventrolateral marginal zone explants (VLMZ). Embryos were ventrally injected at 4-cell stage with bmpr1a-EYFP and memb-RFP mRNA with Mo. VLMZs were dissected at stage 11.5 for IF. g IF for Bmpr1a (green) and cell membrane (memb-RFP, red) in VLMZ injected with mRNA and Mo as indicated. Scale bar, 20 μm. h Quantification of g. n = the number of areas analyzed and data are displayed as mean ± SD. **P < 0.01, ***P < 0.001 from two-tailed unpaired t-test. i Western blot analysis of Bmpr1a in Xenopus laevis neurulae (St. 18) injected radially at 4-cell stage as indicated. Gapdh, a loading control. Data shows representative result from 2 independent experiments with similar conclusion.
	Fig. 7: RSPO2 requires ZNRF3 to antagonize BMP4-BMPR1A signaling. a BRE reporter assay in HEPG2 cells. Cells were transfected with siControl or siZNRF3/siRNF43, and BMP4 with or without RSPO1-4 were added overnight as indicated. Normalized BRE activity upon BMP4 without RSPO2 stimulation was set to 100%. n = 3 biologically independent samples. b BRE reporter assay in HEPG2 cells upon ZNRF3ΔR transfection, with or without overnight BMP4 and RSPO2 treatment as indicated. n = 3 biologically independent samples. c BMP-reporter (vent2) assay in Xenopus laevis St.15 neurulae. Embryos were injected animally with reporter plasmids and the indicated Mo with or without rspo2 mRNA at 4-cell stage. Normalized vent2 activity of control Mo injected embryos with reporter plasmids was set to 1. n = 3 biologically independent samples. d Immunofluorescence microscopy (IF) in Xenopus laevis animal cap explants for Bmpr1a (green) and the plasma membrane (red) from embryos injected with mRNA as indicated, with a representative cell (top) and magnification (inset). Scale bar, 20 μm. For scheme, see Fig. 6c. e Quantification of d. n = areas analyzed and data are displayed as mean ± SD. ns, not significant, ****P < 0.0001 from one-way ANOVA analysis. f–g BRE reporter assay in HEPG2 cells treated with BMP4 and RSPO2/RSPO2ΔFU1/RSPO2ΔFU2 overnight as indicated. For domain structure of RSPO2ΔFU1/RSPO2ΔFU2, see Supplementary Fig. 8a. n = 3 biologically independent samples. h IF for Bmpr1a (green) and plasma membrane (red) in animal cap explants injected as indicated, with a representative cell (top) and magnification (inset) showing the plasma membrane. Scale bar, 20 μm. For domain structure of Xenopus Rspo2 mutants, see Supplementary Fig. 8d. i Quantification of h. n = areas analyzed and data are displayed as mean ± SD. ns, not significant, ****P < 0.0001 from one-way ANOVA analysis. All data are displayed as mean ± SD. The P values for reporter assays (a–c, f, g) were determined from two-tailed unpaired t-test. ns, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
	Fig. 8: RSPO2 bridges BMPR1A and ZNRF3 and triggers BMP receptor clearance from the cell surface.. a, b In vitro binding assay between ZNRF3 and BMPR1AECD mediated by RSPO1-3. ZNRF3-Fc protein was used as a bait, with sequential RSPO1-3 protein and BMPR1AECD-AP treatment. Bound BMPR1AECD to ZNRF3 was detected by chromogenic AP assay. n = 3 experimentally independent samples. c, d IF in H1581 cells transfected with BMPR1A-HA and ZNRF3-flag DNA upon RSPO2 and RSPO3-HRP treatment for 3 h. RSPOs (red) were visualized with tyramid signal amplification. BMPR1A (blue) and ZNRF3 (green) were stained against HA and flag antibody. White arrowheads, colocalized BMPR1A/RSPO2; white arrows, colocalized BMPR1A/RSPO2-3/ZNRF3; yellow arrow, colocalized BMPR1A/RSPO2-3/ZNRF3 in magnified inset; Dashed lines, nucleus. Scale bar, 20 μm. e–h IF of colocalized BMPR1A (green)/ZNRF3 (red) in H1581 cells treated with siRNA as indicated. Nuclei were stained with Hoechst. Scale bar, 20 μm. i Quantification of BMPR1A colocalizing with ZNRF3 from e–h. j–l IF of BMPR1A (green) in H1581 cells treated with siRNA as indicated. m Quantification of cells harboring membrane localized BMPR1A from j–l. Scale bar, 20 μm. n Cell surface biotinylation assay in H1581 cells treated with BMPR1A-HA and siRNA as indicated. Co, control; R2, RSPO2; ZR, ZNRF3/RNF43 siRNA. After labeling surface proteins with Biotin, lysates were pulled down with streptavidin beads and subjected to Western blot analysis. Transferrin receptor (TfR), a loading control. TCL, Total cell lysate. Data shows results representative for 2 from 3 independent experiments. o BRE reporter assay in HEPG2 cells treated as indicated. MDC, monodansylcadaverin. n = 3 biological replicates. p IF of colocalized BMPR1A (green)/EEA1 (magenta) in H1581 cells treated with siRNA. White arrowheads, colocalized BMPR1A/EEA1 in magnified inset. q Quantification of p. Scale bar, 20 μm. r IF of colocalized BMPR1A (green)/Lamp1 (red) in H1581 cells treated with siRNA as indicated. White arrowheads, colocalized BMPR1A/Lamp1 in magnified inset. Scale bar, 20 μm. s Quantification of r. For i, m, q, s, n = the number of cells pooled from 2 independent experiments. Data for (a, b, i, m, o, q, s) are displayed as mean ± SD. ns, not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 from two-tailed unpaired t-test.
	Supplementary Fig. 1
	Supplementary Fig. 2
	Supplementary Fig. 3
	Supplementary Fig. 4
	Supplementary Fig. 5
	Supplementary Fig. 6
	Supplementary Fig. 7
	Supplementary Fig. 8
	Supplementary Fig. 9
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	Supplementary Fig. 11

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