Rankin SA , Gallas AL , Neto A , Gómez-Skarmeta JL , Zorn AM .

DK70858 NIDDK NIH HHS , R01 DK070858 NIDDK NIH HHS

             trachea development
             esophagus development

Xtr Wt + BIO (fig.4.e)
Xtr Wt + BIO (fig.5.g)
Xtr Wt + BIO + CHX (fig.4.e)
Xtr Wt + BIO + CHX (fig.4.e)
Xtr Wt + BIO + RA (fig.5.g)
Xtr Wt + BIO + su5402 (fig.4.e)
Xtr Wt + BIO + su5402 (fig.4.e)
Xtr Wt + BMS493 (fig.4.d)
Xtr Wt + BMS493 (fig.S6.a)
Xtr Wt + BMS493 (fig.S6.b)
Xtr Wt + BMS493 (fig.S6.b)
Xtr Wt + CHX (fig.4.e)
Xtr Wt + LDN-193189 (fig.6.c)
Xtr Wt + LDN-193189 (fig.S8.b)
Xtr Wt + LDN-193189 (fig.S8.d1,d2,d3)
Xtr Wt + LDN-193189 (fig.S8.d3,d4)
Xtr Wt + Mmu.osr1-GR + DEX (fig.7.a)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.2.b)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.2.b,e,e^1)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.2.e,e^1)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.2.h)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.2.h,k,k^1)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.2.k)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.2.k^1)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.S3)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.S3)
Xtr Wt + Mmu.osr1-GR + osr1 MO + osr2 MO (fig.S3)
Xtr Wt + PD173074 (fig.4.b)
Xtr Wt + RA (fig.5.g)
Xtr Wt + XAV939 (fig.4.c)
Xtr Wt + osr1 MO + osr2 MO (fig.1.j)
Xtr Wt + osr1 MO + osr2 MO (fig.1.l)
Xtr Wt + osr1 MO + osr2 MO (fig.1.n, n')
Xtr Wt + osr1 MO + osr2 MO (fig.3.b,b^1)
Xtr Wt + osr1 MO + osr2 MO (fig.3.e,e^1)
Xtr Wt + osr1 MO + osr2 MO (fig.5.d)
Xtr Wt + osr1 MO + osr2 MO (fig.5.g)
Xtr Wt + osr1 MO + osr2 MO (fig.6.a)
Xtr Wt + osr1 MO + osr2 MO (fig.6.b)
Xtr Wt + osr1 MO + osr2 MO (fig.6.c)
Xtr Wt + osr1 MO + osr2 MO (fig.6.c)
Xtr Wt + osr1 MO + osr2 MO (fig.S2.b)
Xtr Wt + osr1 MO + osr2 MO (fig.S2.c)
Xtr Wt + osr1 MO + osr2 MO (fig.S5.b)
Xtr Wt + osr1 MO + osr2 MO (fig.S7.a)
Xtr Wt + osr1 MO + osr2 MO (fig.S7.d)
Xtr Wt + osr1 MO + osr2 MO + BIO (fig.5.e)
Xtr Wt + osr1 MO + osr2 MO + BIO (fig.5.g)
Xtr Wt + osr1 MO + osr2 MO + BIO + RA (fig.5.g)
Xtr Wt + osr1 MO + osr2 MO + RA (fig.5.f)
Xtr Wt + osr1 MO + osr2 MO + RA (fig.5.g)
Xtr Wt + smad1-Rno.GR + DEX ( fig.S7.c)
Xtr Wt + smad1-Rno.GR + DEX (fig.S7.b)
Xtr Wt + su5402 (fig.4.e)
Xtr Wt + su5402 (fig.4.e)
Xtr Wt + wnt2b MO (fig.S5.c)
Xtr Wt + wnt2b MO (fig.S5.c)
Xtr Wt + {dn}tcf3-GR + DEX (fig.S5.a)

	Fig. 1. osr1 and osr2 are dynamically expressed in the developing Xenopus foregut and are required for lung development. (A-G′′) In situ hybridization of osr1 (A-D) and osr2 (E-H) expression in Xenopus tropicalis embryos and isolated gut tubes (D,H) at the indicated stages (st), anterior leftwards, dorsal upwards. Stage 15 embryos (A,E) are bisected and stage 33 embryos (C′-C[H11630],G′-G[H11630]) are sectioned to show the endoderm (outlined in yellow in A,E). fg, foregut; hg, hindgut; de, dorsal endoderm; pe, posterior endoderm; e, esophagus; l/t, presumptive lung and trachea; lv, liver; lpm, lateral plate mesoderm; k, kidney; s, stomach. (I-N′) surfactant protein c (sftpc) (I-L) and nkx2.1 (M,N′) expression in embryos injected on one side with Osr1/Osr2-MOs (10 ng each) or negative control mutated oligos MM-MO (20 ng) shows lung agenesis on the Osr1/Osr2-depleted side. (M’-N′) Sections. Numbers of embryos with the shown phenotype are indicated. Dorsal view of an isolated gut tube (K,L) shows the lung bud absent on the injected side (red arrow).
	Fig. 2. Osr1/Osr2 are required for respiratory specification and tracheal-esophageal separation. (A-L′) Embryos were co-injected with control MM-MOs or Osr1/Osr2-MOs and GR-mOsr1 RNA (250 pg) in both dorsal-vegetal blastomeres at the eight-cell stage (bilateral injection) and then cultured ±dexamethasone from stage 20 onwards. (A-C,G-I) Analysis by in situ hybridization of nkx2.1 at stage 34/35 (A-C) and sftpc at stage 42 (G-I). (D-F′,J-L′) Confocal immunofluorescence of Nkx2.1 (green) and Sox2 (red) at stage 35/36 (D-F) and stage 42 (J-L). es, esophagus; tr, trachea; lb, lung buds; st, stomach, Scale bars: 100 μm. [Curators Note: all embryos X. laevis]
	Fig. 3. Osr1/Osr2 are required for wnt2b and raldh2 expression in the lpm. (A-X) Analysis of stage 34/35 unilateral-injected embryos shows that Osr1/Osr2 are required for expression of nkx2.1 (A-C) and sox2 (D-F) in the epithelium, whereas shh (G-I) is unaffected. In the lpm, wnt2b (J-L) and raldh2 (M-O) are absent, while foxf1 is unaffected (P-R). Black arrows indicate normal expression on the control side and red arrows indicate lack of expression on the Osr1/Osr2-MO-injected side (right). Endoderm outlined by a yellow line. Numbers of embryos with the shown phenotype are indicated. fg, foregut; hg, hindgut; de, dorsal endoderm; pe, posterior endoderm; e, esophagus; l/t, presumptive lung and trachea; lv, liver; lpm, lateral plate mesoderm; k, kidney; s, stomach.
	Fig. 4. FGF, Wnt/β-catenin and RA signaling regulate Xenopus lung development in a pathway with Osr1/Osr2. (A-D) Embryos were treated from stages 25-35 with DMSO vehicle (A), 100 μM PD173074 (B), 50 μM XAV939 (C) or 10 μM BMS493 (D), and assayed at stage 35 with the indicated probes. (E). Embryos were treated between stages 28 and 35 with vehicle (DMSO), 10 μM BIO, 80 μM SU5402, a combination of 80 μM SU5402 + 10 μM BIO, 10 μg/ml cycloheximide (CHX) or CHX +10 μM BIO, and analyzed for nkx2.1 at stage 35 and sftpc at stage 40. Black arrows indicate normal expression, red arrows indicate absent expression, yellow arrows indicate reduced expression and green arrows indicate expanded or rescued expression.
	Fig. 5. Osr1/Osr2 act upstream of Wnt-mediated pulmonary specification and RA-regulated lung bud growth. (A-G) Osr1/Osr2-MO- and MM-MO-injected embryos were treated at stages 25-35 with DMSO vehicle, 10 μM BIO or 1 μM all-trans-retinoic acid (RA), and analyzed for nkx2.1, sox2, wnt2b and raldh2 at stage 35 (A-F) and sftpc at stage 42 (dorsal view) (G). Black arrows indicate normal expression, red arrows show absent expression, green arrows and lines indicate expanded expression and white arrows indicate rescued expression.
	Fig. 6. Osr1/Osr2 promotes lung specification and growth by restricting BMP signaling. (A). Analysis of Osr1/Osr2-MO and control MM-MO stage 35 embryos indicated that expression of bmp4 and BMP-target genes msx1 and hand1 are expanded into the ‘wnt2b-domain’ of the lpm on the Osr1/Osr2-depleted side. Black arrows indicate normal expression, red arrows indicate absent expression and green arrows indicate enhanced expression. (B) Confocal immunostaining of stage 35 embryos for phospho-Smad1/5/8 (green) and fibronectin (red). Scale bars: 50 μm. White arrows in B indicate ectopic pSMAD1 expression in dorsal foregut endoderm. (C) Analysis of nxk2.1, sox2, wnt2b and raldh2 at stage 35 or sftpc at stage 41 in embryos injected with Osr1/Osr2-MOs or MM-MOs and treated at stages 25-35 with either DMSO (vehicle control) or 10 μM LDN193189. Insets show ventral views of wnt2b expression. For analysis of sftpc expression at stage 41, embryos were removed from the LDN193189 at stage 35 and further cultured in DMSO vehicle until stage 41. Black arrows indicate normal expression, red arrows indicate absent expression, green arrows indicate expanded expression and white arrows indicate rescued expression.
	Fig. 7. Osr1/Osr2 can repress bmp4 expression. (A) GR-mOsr1 RNA (750 pg) was injected into both dorsal-vegetal cells at the eight-cell stage and embryos were dexamethasone treated at stage 20 to induce the construct and analyzed at stage 34/35 for expression of the indicated genes. Insets show ventral views of wnt2b expression. (B) The X. laevis bmp4 promoter construct, showing two putative odd-skipped-binding sites. Green sequence indicates consensus odd skipped-binding site, red sequence is the exact bmp4 promoter sequence, and mutations to these sites are shown below indicated by ‘δ’ and in black. (C) RNA (750 pg) encoding Xenopus, mouse or Drosophila Osr factors was co-injected with the –2123 bmp4: luciferase reporter at the 32-cell stage and luciferase activity was assayed at stage 12. Average relative activity ±s.d. (D) Xenopus Osr1 or Osr2 RNA (750 pg) was co-injected with the wild-type bmp4 reporter or the mutated reporter constructs indicated in B, and the resulting average fold repression ±s.d., of the luciferase reporter from three independent experiments was determined. *P<0.005.
	Fig. 8. Model of the molecular pathway regulating Xenopus lung development. Osr1/Osr2 are key components of a molecular pathway regulating respiratory specification in Xenopus. Blue lines indicate relationships tested in this study and black lines indicate relationships predicted from published mouse studies.
	Fig. S1. Analysis of Xenopus foregut gene expression at stage 36/37. (A-E) Wild-type embryos were assayed by in situ hybridization for expression of the indicated genes, and then 30 µm sections through the foregut were prepared and are shown (1 is the anterior most section, followed by 2, then 3). e, esophagus; l/t, lung/trachea; lpm, lateral plate mesoderm; lv, liver; lb, lung bud.
	Fig. S2. Germ layer specification and anterior-posterior patterning are unaffected by knockdown of Osr1 and Osr2 on 1 side of the embryo. (A-D) Embryos were injected at the four/eight-cell stage on 1 side with control MM-MO1+MM-MO2 (10 ng each) or Osr1-MO+Osr2-MO (10 ng each), cultured until (A) gastrula, (B) neurula, (C) tailbud (C) or (D) stage 35, and assayed by in situ hybridization with the indicated probes. The earliest defect observed in Osr1/2-MO embryos was a loss of lim1, pax8 and raldh2 (red arrows) in the intermediate mesoderm of the developing kidney, as previously described (Tena et al., 2007). Liver, pancreas, intestine and heart development are unaffected in Osr1/2 morphants (D). pdx1 expression in the duodenum is modestly reduced by Osr1/2-MOs.
	Fig. S3. The Osr1/2-MO phenotype can be rescued by overexpression of mouse Osr1 RNA. Embryos were co-injected with control MM-MOs or Osr1/2-MOs and GR-mOsr1RNA (250 pg) in both dorsal-vegetal blastomeres at the eight-cell stage (bilateral injection) and then cultured with or without dexamethasone from stage 20 onwards. Analysis by in situ hybridization of nkx2.1, wnt2b, sox2 and bmp4 at stage 34/35 and of sftpc in isolated gut tubes at stage 42. Analysis by immunofluorescence of fibronectin (red), activated caspase 3 (green) and nuclei (blue) at stage 42 show and undivided foregut tube and extensive cell death.
	Fig. S4. Fgf expression, cell proliferation and cell death are unaltered in Osr1/2-depleted embryos. Embryos were injected on one side with Osr1-MO and Osr2-MO, and analyzed at stage 35. (A) In situ hybridization with fgf7 and fgf10 probes and (B) anti-phospho-histone H3 immunohistochemistry or for TUNEL reactivity indicate that there were no changes in cell proliferation of cell death. The histogram shows the average number of positive foregut cells±s.d. (n=10 embryos per condition).
	Fig. S5. Wnt2/2b/β-catenin/Tcf activity is required for Xenopus lung specification. (A) Embryos were injected in one dorsal-vegetal blastomere at the four/eight-cell stage with RNA encoding a hormone-inducible dominant-negative Tcf3 (GR-dNTcf3), which blocks β-catenin/Tcf-responsive transcription (Wnt LOF). Between stages 28 and 35, embryos were treated with or without 1 µM dexamethasone (dex) to activate the GR-dNTcf3. In situ hybridization at stage 35 shows that nkx2.1, but not wnt2b or osr2 expression, is regulated by Tcf. (B) Osr1/2-MO embryos do not express either wnt2 or wnt2b. (C) Wnt2/2b are redundantly required for nkx2.1 expression. X. tropicalis embryos were injected at the four/eight-cell stage in both dorsal-vegetal blastomeres with 20 ng each Wnt2-MO + Wnt2b-MO or 40 ng control MO and assayed at stage 35 for the indicated genes or at stage 42 gut tubes were isolated and assayed for sftpc. Numbers of embryos with the shown phenotype are indicated. Abbreviations: lpm, lateral plate mesoderm; fg, foregut.
	Fig. S6. Retinoic acid signaling is required for Xenopus lung bud growth but not specification. (A,B) Embryos were cultured in 10 µM BMS493, a pan retinoic acid receptor inhibitor, from stages 25 to 35 (A) or stage 25-42 (B), and assayed by in situ hybridization with the indicated probes. (A) Although inhibition of RA signaling did not prevent pulmonary specification (Fig. 3), expression of dkk1 was upregulated as expected based on the finding that Dkk1 is upregulated in Raldh2-/- mutant mouse embryos (Chen et al., 2010). (B) A dorsal view of isolated gut tubes shows that inhibition of RA signaling from stages 25-42 inhibited the growth of sftpc-expressing lung buds.
	Fig. S7. BMP/pSMAD1 signaling is upregulated in Osr1/2-depleted embryos and temporal Smad1 overexpression can inhibit lung specification. (A) Immunofluorescence analysis of phospho-SMAD1/5/8 (green) and fibronectin (red) at stage35/36 in Osr1/2-MO bilaterally injected embryos. Section 1 through the foregut is anterior to section 2. Yellow arrows indicate ectopic pSMAD1/5/8 in dorsal foregut endoderm, and yellow asterisks indicate ectopic pSMAD1/5/8 and reduced fibronectin at the level of the nascent lung buds. (B) Embryos were injected with RNA encoding a hormone-inducible GR-Smad1 (800 pg) at the four/eight-cell stage into 1 side of the embryo. Between stages 25 and 35, embryos were treated with or without 1 µM dexamethasone (dex) to activate the construct, thus inducing active BMP signaling. In situ hybridization at stage 35 shows that activated GR-Smad1 is inhibitory to wnt2b, nkx2.1 and sox2 expression. (C) Overexpression of GR-SMAD1 does not cause cell death. Embryos were injected and treated as in B, and analyzed at stage 35/36 by immunofluorescence for Sox2 (red) and activated caspase 3 (green). No cell death was detectable in either condition. (D) LDN treatment rescues the elevated pSMAD1/5/8 signaling observed in Osr1/2-MO embryos. Embryos were injected as in A and treated from stages 25-35 with DMSO vehicle or 10 µM LDN193189 and assayed by immunofluorescence for phospho-SMAD1/5/8 (green).
	Fig. S8. BMP signaling that function in a time period after respiratory specification is required for trachea formation and lung bud development. (A,B) In situ hybridization of nkx2.1 expression in embryos treated from stages 35-42 with DMSO (vehicle) or 10 µM LDN193189 to inhibit BMP receptor type I signalling. Red arrows show absent trachea and single dismorphic lung bud. Brain, br; trachea, tr; lung bud, lb. (C,D) Immunofluorescence analysis of Nkx2.1 (green) and Sox2 (red) in serial foregut sections (1 is the anterior-most section, 4 is the posterior-most) reveal loss of trachea, expansion of esophagus and lung bud hypoplasia in LDN-treated embryos.
	fibronectin red
	phospho SMAD158 green
	Confocal immunoflurescence of Nkx2-1 AB1 (green) staining trachea and lung buds/lung primordia, along with Sox2 AB1 (red) staining stomach and esophagus, in a NF stage 42 X. laevis embryo.
	Confocal immunoflurescence of Sox2 AB1(red) staining stomach and esophagus and Nkx2-1 AB1 (green) staining trachea and lung buds/lung primordia, in a NF stage 42 X. laevis embryo.
	osr1 (odd skipped related protein 1) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 15, mid-sagittal section, anterior left, dorsal up.
	osr1 (odd skipped related protein 1) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 28, lateral view, anterior left, dorsal up.
	osr1 (odd skipped related protein 1) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 42, isolated gut tube, anterior left.
	osr2 (odd skipped related protein 2) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 15, mid-sagittal section, anterior left, dorsal up.
	osr2 (odd skipped related protein 2) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 28, lateral view, anterior left, dorsal up.
	osr2 (odd skipped related protein 2) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 42, isolated gut tube, anterior left.
	sftpc (surfactant, pulmonary-associated protein C ) gene expression in Xenopus tropicalis embryo, assayed via in situ hybridization, NF stage 42, isolated gut tube, anterior left.
	wnt2b (wingless-type MMTV integration site family member 2B) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34/35, lateral view, anterior left, dorsal up.
	shh (sonic hedgehog) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34/35, lateral view, anterior left, dorsal up.
	aldh1a2 (aldehyde dehydrogenase 1 family member A2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34/35, lateral view, anterior left, dorsal up.
	sox2 (SRY-box 2) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34/35, lateral view, anterior left, dorsal up.
	foxf1 (forkhead box F1 ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 34/35, lateral view, anterior left, dorsal up.
	sftpc (surfactant, pulmonary-associated protein C ) gene expression in Xenopus laevis embryo, assayed via in situ hybridization, NF stage 41, ventral view view, anterior up.

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