XB-ART-45729
Dev Cell
2012 Aug 14;232:292-304. doi: 10.1016/j.devcel.2012.07.002.
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Sizzled-tolloid interactions maintain foregut progenitors by regulating fibronectin-dependent BMP signaling.
Kenny AP
,
Rankin SA
,
Allbee AW
,
Prewitt AR
,
Zhang Z
,
Tabangin ME
,
Shifley ET
,
Louza MP
,
Zorn AM
.
???displayArticle.abstract???
The liver, pancreas, and lungs are induced from endoderm progenitors by a series of dynamic growth factor signals from the mesoderm, but how the temporal-spatial activity of these signals is controlled is poorly understood. We have identified an extracellular regulatory loop required for robust bone morphogenetic protein (BMP) signaling in the Xenopus foregut. We show that BMP signaling is required to maintain foregut progenitors and induce expression of the secreted frizzled related protein Sizzled (Szl) and the extracellular metalloprotease Tolloid-like 1 (Tll1). Szl negatively regulates Tll activity to control deposition of a fibronectin (FN) matrix between the mesoderm and endoderm, which is required to maintain BMP signaling. Foregut-specific Szl depletion results in a loss of the FN matrix and failure to maintain robust pSmad1 levels, causing a loss of foregut gene expression and organ agenesis. These results have implications for BMP signaling in diverse contexts and the differentiation of foregut tissue from stem cells.
???displayArticle.pubmedLink??? 22863744
???displayArticle.pmcLink??? PMC3615545
???displayArticle.link??? Dev Cell
???displayArticle.grants??? [+]
DK070858 NIDDK NIH HHS , K08 HL105661 NHLBI NIH HHS , P30 DK078392 NIDDK NIH HHS , R01 DK070858 NIDDK NIH HHS , T32 HD07463 NICHD NIH HHS , T32 HD007463 NICHD NIH HHS
Species referenced: Xenopus laevis
Genes referenced: bmp1 bmp2 bmp4 bmp7.1 chrd fbn1 fn1 frzb2 hhex nr1h5 nr2e1 pdx1 smad1 szl tll1 ventx2
???displayArticle.morpholinos??? bmp1 MO1 bmp2 MO1 fn1 MO1 fn1 MO2 szl MO1 tll1 MO1
???displayArticle.gses??? GSE38654: NCBI
Phenotypes: Xla Wt + Caspase Inhibitor I (fig.3.c) [+]
Xla Wt + Hsa.BMP2
(fig.1.c)
Xla Wt + Hsa.BMP2 (fig.1.c)
Xla Wt + Hsa.BMP4 (fig.S4.b)
Xla Wt + LDN-193189 (fig.5.b)
Xla Wt + LDN-193189 (fig.6.h)
Xla Wt + LDN-193189 (fig.8.a)
Xla Wt + LDN-193189 (fig.8.a)
Xla Wt + bmp2 MO (fig.1.c)
Xla Wt + bmp2 MO (fig.2.f)
Xla Wt + bmp2 MO (fig.2.j)
Xla Wt + bmp2 MO (fig.2.l)
Xla Wt + bmp2 MO (fig.2.n)
Xla Wt + bmp2 MO (fig.2.p)
Xla Wt + bmp2 MO (fig.2.r)
Xla Wt + bmp2 MO (fig.2.t)
Xla Wt + bmp2 MO (fig.5.b)
Xla Wt + fn1 MO (fig.8.a)
Xla Wt + fn1 MO (fig.8.a)
Xla Wt + fn1 MO (fig.S6)
Xla Wt + fn1 MO (fig.S6)
Xla Wt + szl MO (fig.3.a, b, d)
Xla Wt + szl MO (fig.3.c)
Xla Wt + szl MO (fig.3.c)
Xla Wt + szl MO (fig.5.b)
Xla Wt + szl MO (fig.5.d)
Xla Wt + szl MO (fig.6.j)
Xla Wt + szl MO (fig.6.n)
Xla Wt + szl MO (fig.6.r)
Xla Wt + szl MO (fig.7.a)
Xla Wt + szl MO (fig.8.a)
Xla Wt + szl MO (fig.8.a)
Xla Wt + szl MO (fig.8.a)
Xla Wt + szl MO (fig.S2.c)
Xla Wt + szl MO (fig.S2.c)
Xla Wt + szl MO (fig.S2.d)
Xla Wt + szl MO (fig.S2.d)
Xla Wt + szl MO (fig.S4.a)
Xla Wt + Hsa.BMP2 (fig.1.c)
Xla Wt + Hsa.BMP4 (fig.S4.b)
Xla Wt + LDN-193189 (fig.5.b)
Xla Wt + LDN-193189 (fig.6.h)
Xla Wt + LDN-193189 (fig.8.a)
Xla Wt + LDN-193189 (fig.8.a)
Xla Wt + bmp2 MO (fig.1.c)
Xla Wt + bmp2 MO (fig.2.f)
Xla Wt + bmp2 MO (fig.2.j)
Xla Wt + bmp2 MO (fig.2.l)
Xla Wt + bmp2 MO (fig.2.n)
Xla Wt + bmp2 MO (fig.2.p)
Xla Wt + bmp2 MO (fig.2.r)
Xla Wt + bmp2 MO (fig.2.t)
Xla Wt + bmp2 MO (fig.5.b)
Xla Wt + fn1 MO (fig.8.a)
Xla Wt + fn1 MO (fig.8.a)
Xla Wt + fn1 MO (fig.S6)
Xla Wt + fn1 MO (fig.S6)
Xla Wt + szl MO (fig.3.a, b, d)
Xla Wt + szl MO (fig.3.c)
Xla Wt + szl MO (fig.3.c)
Xla Wt + szl MO (fig.5.b)
Xla Wt + szl MO (fig.5.d)
Xla Wt + szl MO (fig.6.j)
Xla Wt + szl MO (fig.6.n)
Xla Wt + szl MO (fig.6.r)
Xla Wt + szl MO (fig.7.a)
Xla Wt + szl MO (fig.8.a)
Xla Wt + szl MO (fig.8.a)
Xla Wt + szl MO (fig.8.a)
Xla Wt + szl MO (fig.S2.c)
Xla Wt + szl MO (fig.S2.c)
Xla Wt + szl MO (fig.S2.d)
Xla Wt + szl MO (fig.S2.d)
Xla Wt + szl MO (fig.S4.a)
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Figure 1. Mesodermal BMP2 Signals Maintain Foregut Progenitors and Induce szl(A) Strategy to identify genes induced in the foregut progenitors (fg; green) by the precardiac mesoderm (cm; red).(B) BMP and FGF pathway genes identified by microarray.(C) In situ hybridization to bisected stage 20 embryos (anterior left) and isolated ventral explants cultured from stage 15 to 23 with or without mesoderm confirms that szl and hhex expression requires mesodermal signals. Injection of cont-MO, bmp2-MO, or BMP2 protein demonstrates that szl and hhex expression are regulated by BMP signaling.(D) Bisected stage 20 embryos (anterior left) showing bmp2, bmp4, and bmp7 expression in the precardiac (cm) and the ventral lateral plate mesoderm (lpm).See also Figure S1. |
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Figure 3. Szl Depletion Results in Foregut Progenitor Apoptosis(A) Szl depletion causes increased foregut cell apoptosis. Mean number of activated caspase-3 cells SEM in the foreguts of stage 20 embryos injected with cont-MO (20 ng), szl-MO (15 ng), and/or szl-DNA (500 pg) from three independent injection experiments. In Student's t tests p < 0.05 ∗compared to cont-MO and ∗∗compared to szl-MO.(B) Apoptosis was specific to the foregut. The szl-MO (20 ng) was injected in all cells of 4-cell stage embryos and the mean number of activated caspase-3 positive cells SEM in the foregut, hindgut and ectoderm was scored from five stage 20 embryos. ∗p < 0.05 comparing cont-MO to szl-MO; ns, not significant.(C and D) Cell death cannot account for loss of foregut identity. szl-MO-injected embryos treated at stage 12 with one of three different caspase inhibitors (n > 10 per inhibitor). In each case, szl-MO embryos still exhibit reduced hhex and for1 (C) even when cell death was rescued (D). A representative experiment is shown.Error bars reflect SEM. |
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Figure 4. pSmad1 Dynamics in the Xenopus Foregut(A) Diagram of a stage 20 Xenopus embryo section showing the foregut (fg) region in green that was isolated for western blots and imaged by confocal.(B) Immunoblot of pSmad1/5/8, total Smad1 and tubulin levels in foregut explants at the indicated developmental stages, with the pSmad1/total Smad1 ratio quantitated above.(C) Immunostaining of pSmad1/5/8 (red) and nuclei (green) in the foregut of bisected embryos at the indicated stage shows spatially and temporally dynamic BMP signaling in the foregut. White dashed lines indicate the boundaries between the endoderm (end), mesoderm (m), and ectoderm (ect). |
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Figure 5. Szl Is Required to Maintain Robust BMP Signaling in the Foregut(A) Western blot of pSmad1/5/8 and total Smad1 in foregut explants from cont-MO and szl-MO embryos at different stages shows reduced BMP signaling in Szl morphants.(B) Szl-depleted embryos exhibit reduced pSmad1 signaling in the foregut. Fifty micrometer confocal Z-projections of pSmad1/5/8 (green) and nuclei (red) in stage 20 sibling embryos injected with cont-MO (20 ng), szl-MO (15 ng), or bmp2-MO (20 ng) or treated with BMP-receptor inhibitor LDN193189 (40 μM). Yellow dashed lines indicate the mesoderm-endoderm boundary. Dashed white lines in nuclear channel of the cont-MO illustrate the subregion of the foregut, based on number of nuclei from the mesoderm. See also Figure S3.(C) Szl- and Bmp2-depleted embryos have reduced pSmad1 levels in the deep foregut endoderm. Mean nuclear/cytoplasmic ratio of pSmad1 immunostaining intensity SEM in foregut cells at different distances from the mesoderm, quantitated from 80 μm Z-projections from four sibling embryos/condition. ∗Significantly different from szl-MO, p < 0.05.(D) Expression of bmp2, bmp4/7, and BMP-target genes szl, vent1/2, and hhex were downregulated by injection of the szl-MO (15 ng) and rescued by subsequent injection of recombinant BMP2 protein (4 ng) into the foregut at stage 12.(E) Mean number of activated caspase-3 positive foregut cells SEM (n = 5 embryos / condition), ∗p < 0.01 in Student t tests.Error bars reflect SEM. |
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Figure 6. Knockdown of Tll Proteases Rescues the szl-MO Phenotype(A) Expression of szl, tll1, bmp1, and chordin in stage 18 embryos.(E) tll1 expression in embryos injected in the C1/D1 cells with control-MO (20 ng), szl-MO (15 ng), bmp2-MO (20 ng) or treated with BMP-receptor inhibitor LDN193189 (40 μM).(I) Knockdown of Tll1 and Bmp1 rescues the Szl morphant phenotype. tll1-MOs and bmp1-MOs (15 ng each) were injected into C1/D1 cells with or without szl-MO (15 ng) and assayed for hhex (I) and vent1/2 (M) at stage 20 and the liver marker for1 at stage 35 (Q).See also Figure S4. |
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Figure 7. Loss of FN Matrix in szl-MO(A) FN and β1-integrin immunostaining (10 μm confocal slice) of cont-MO and szl-MO-injected foreguts at stage 180 shows that the FN matrix between the endoderm (end) and mesoderm (mes) (yellow arrows) is absent in szl-MO (red arrows). Yellow dashed lines outline the precardiac lateral plate mesoderm.(B) Western blots of foregut explants show no obvious degradation of FN or β1-integrin in Szl morphants. The relative FN/tubulin and integrin/tubulin levels in the szl-MO compared to the cont-MO, which was set to 1.0 is indicated.See also Figure S5. |
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Figure 8. Szl-Tll Regulates FN Matrix Assembly, which Is Required to Maintain BMP Signaling(A) Embryos injected with cont-MO (20 ng), szl-MO (15 ng), cont-MO + bmp1-MO + tll1-MO (15 ng each), szl-MO + bmp1-MO + tll1-MO (15 ng each), or fn-MOs (15 ng) or treated with BMP-receptor inhibitor LDN193189 (40 μM). Confocal FN immunostaining (10 μm slice) shows FN fibrils (yellow arrow heads) between the foregut endoderm (end) and mesoderm (m), which are disrupted in szl-MO and fn-MO-injected embryos (red arrow heads). Confocal immunostaining of pSmad1 (green) and nuclei (red) in the foregut endoderm (50 μm Z-projection four to nine nuclei from the mesoderm) and in situ for bmp2, bmp4/7, and hhex indicate that BMP signaling was reduced in szl-MO, fn-MO, and LDN-treated embryos. Knockdown of Bmp1/Tll1 rescues the FN matrix, pSmad1 levels and BMP-responsive gene expression in Szl morphants. See also Figure S6.(B) Mean nuclear/cytoplasmic pSmad1 immunostaining intensity SEM in foregut cells located four to nine nuclei from the mesoderm, quantitated from 80 μm Z-projection from four sibling embryos/condition. Significantly different from contMO in t test: ∗p < 0.05, ∗∗LS mean difference > 0.3; p < 0.01; ns, not significant.(C) Mean number of activated caspase-3 foregut cells SEM. ∗p < 0.05 compared to cont-MO.Error bars reflect SEM. |
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bmp1 (bone morphogenetic protein 1) gene expression in bisected Xenopus laevis embryo, mid-sagittal section, assayed via in situ hybridization, NF stage 18/19, dorsal right, anterior up. |
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Figure S1. Developmental expression of szl, bmp2, bmp4, bmp7 and hhex. In situ hybridization to a stage series of Xenopus laevis embryos with the progressive steps in foregut organogenesis indicated on the left. Embryos stages 10.5-20 are bisected. Stage 10.5 gastrula embryos are oriented dorsal left and ventral right. All other stages are anterior left and ventral down. In the gastrula hhex and bmp2 are expressed in the dorsal mesendoderm, whereas szl, bmp4 and bmp7 are expressed on the opposite side of the embryo in the ventral mesoderm. After gastrulation this szl-, bmp4- and bmp7-expressing tissue has moved to the ventral-posterior side (stage 18-20), at which point szl, bmp2 and bmp7 are also expressed in the ventral foregut and precardiac mesoderm. ss, somite stage. |
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Figure S2. Targeted injection of the szl-MO into the foregut does not disrupt gastrula axial pattering. Embryos were either (A) uninjected or injection with the szl-MO (20 ng) into (B) C1/D1 cells at the 16-cell stage, which give rise to the foregut or (C) injected into ventral cells at the 4-cell stage. Injection of szl-MO into the C1/D1 presumptive foregut (B) did not alter gastrula stage axial pattering as indicated by no change in hhex or szl expression in the organizer or ventral mesoderm respectively, and no alterations in pSmad1/5/8 immunostaining. In contrast injection of the szl-MO into the ventral cells of the 4-cell- stage embryo resulted in axial pattering defects with elevated pSmad1/5/8, expanded expression of szl (a bmp-target) and a loss of hhex, all of which are consistent with previously published work showing that Szl in the gastrula mesoderm regulates axial pattering by repressing BMP signaling. Thus injection of the szl-MO into different regions of the embryos reveals distinct temporal and spatial Szl functions. |
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Figure S2. Targeted injection of the szl-MO into the foregut does not disrupt gastrula axial pattering. Embryos were either (A) uninjected or injection with the szl-MO (20 ng) into (B) C1/D1 cells at the 16-cell stage, which give rise to the foregut or (C) injected into ventral cells at the 4-cell stage. Injection of szl-MO into the C1/D1 presumptive foregut (B) did not alter gastrula stage axial pattering as indicated by no change in hhex or szl expression in the organizer or ventral mesoderm respectively, and no alterations in pSmad1/5/8 immunostaining. In contrast injection of the szl-MO into the ventral cells of the 4-cell- stage embryo resulted in axial pattering defects with elevated pSmad1/5/8, expanded expression of szl (a bmp-target) and a loss of hhex, all of which are consistent with previously published work showing that Szl in the gastrula mesoderm regulates axial pattering by repressing BMP signaling. Thus injection of the szl-MO into different regions of the embryos reveals distinct temporal and spatial Szl functions. |
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Figure S2. Targeted injection of the szl-MO into the foregut does not disrupt gastrula axial pattering. (D) Expression of hhex at stage 32 and nkx2.1 in the lung buds of stage 42 isolated gut tubes shows that embryos injected with the szl-MO (20 ng) lack foregut organs and this can be rescued by sequential injection of the szl-MO and a szl expression plasmid (500 pg). |
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Figure S4. Injection of Chordin protein does not rescue the foregut specific Szl loss of function phenotype. (A) hhex expression in embryos injected into the anterior mesendoderm with control or szl-MO (15 ng) at the 16-cell-stage followed by injection into the foregut blastocoel at stage 12-13 with either recombinant BSA (40 ng), BMP2 (20 ng) or Chordin (40 ng) proteins. (B) In situ hybridization of chordin and szl expression in bisected gastrula that have been injected into the blastocoel at stage 9 with BSA (40 ng), BMP4 (20 ng) or BMP4 (20 ng) + Chordin (40 ng) confirms that the Chordin protein used in (A) was biologically active and can repress the ventralizing activity of BMP4. |
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Figure S5. Fibronectin expression in the Xenopus foregut. (A) Immunostaining of FN (red) and GFP (green) in hhex:gfp transgenic stage 18 embryos reveals a FN fibril layer between the precardiac mesoderm (mes) and the foregut endoderm (end) as well as between the mesoderm and ectoderm (ect). (A) FN channel only. Other ECM proteins were not detected in the foregut including: Fibrillin (B and B, Collagen Type II (D and D, pan-Collagen types I-V (F and F and Laminin (H and H. Positive control staining of stage 32 embryos revealed strong expression around the notochord (N) and neural tube (C, E, G, and I). All images are 10 m confocal slices. |
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Figure S6. Characterization of fn-MO injected embryos. Embryos were injected with either control-MO or fibronectin-MOs (a combination of fn1- MO and fn2-MO; 15 ng each), which target both fn genes in the C1/D1 cells of the 16- cell stage embryo, which targets the anterior mesendoderm. FN immunostaining (80 m Z-projection) of the foregut at stage 20 shows that the pericellular FN matrix as well as the FN fibril layer between the mesoderm (mes) and endoderm (end) (yellow arrows) is absent in fn-MO embryos (red arrows), whereas the FN layer between the mesoderm and ectoderm (ect) is still present. hhex expression in the foregut is reduced at stage (st) 20 in fn-MO, but in the gastrula (Stage 10.5) hhex expression is unaltered. At stage 35 fn-MO exhibit reduced the liver marker for1 and cardia bifida as shown by the heart marker c-troponin. Controls injecting the fibronectin-MOs into all cells of the 4-cell stage embryo resulted in frequent gastrulation defects. |
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