Sizzled-Tolloid Interactions Maintain Foregut Progenitors by Regulating Fibronectin-Dependent BMP Signaling

Kenny, Alan P.; Rankin, Scott A.; Allbee, Andrew W.; Prewitt, Allison; Zhang, Zheng; Tabangin, Meredith E.; Shifley, Emily T.; Louza, Mariana P.; Zorn, Aaron M.

doi:10.1016/j.devcel.2012.07.002

Cited by 20 publications

(31 citation statements)

References 54 publications

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“…After gastrulation, at stage NF20, nβ-catenin was still low in the FG and high in the HG; however, we observed an upregulation of pSmad1 levels in the ventral (but not dorsal) FG (Fig. 1F), consistent with the known de novo expression of bmp2/4/7 in the pre-cardiac FG mesoderm (Kenny et al, 2012). Thus, during FG-HG patterning, BMP and Wnt are differentially active along orthologous axes; pSmad1 is high in the ventral and low in the dorsal FG and HG, whereas nβ-catenin is low in the FG and high in the HG (Fig.…”

Section: Bmp and Wnt Regulate Gut Tube Patterningsupporting

confidence: 71%

“…Within the mesoderm, these same Wnt antagonists also promote anterior lateral plate and cardiac fates (reviewed by Gibb et al, 2013;Klaus and Birchmeier, 2009), thus coordinating the development of the FG endoderm and mesoderm lineages. The effects of these pathways on patterning are temporally restricted such that, several hours later, spatially distinct Wnt and/or BMP signals no longer suppress FG identity but promote lung, thyroid, liver, pancreas and heart organogenesis (Kenny et al, 2012;Klaus and Birchmeier, 2009;Zorn and Wells, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs

et al. 2017

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Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how these signals are interpreted in the genome is poorly understood. Here we identified the transcriptomes of Xenopus foregut and hindgut progenitors, which are conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/β-catenin acts as a genome-wide toggle between foregut and hindgut programs. Unexpectedly, β-catenin and Smad1 binding were associated with both transcriptional activation and repression, with Wnt-repressed genes often lacking canonical Tcf DNA binding motifs, suggesting a novel mode of direct repression. Combinatorial Wnt and BMP signaling was mediated by Smad1 and β-catenin co-occupying hundreds of cisregulatory DNA elements, and by a crosstalk whereby Wnt negatively regulates BMP ligand expression in the foregut. These results extend our understanding of gastrointestinal organogenesis and of how Wnt and BMP might coordinate genomic responses in other contexts.

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Section: Bmp and Wnt Regulate Gut Tube Patterningsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs

et al. 2017

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“…Various ECM components, including collagen, fibronectin and laminin have been shown to stimulate pathway activation in response to Bmp ligands (Endo et al, 2012;Paralkar et al, 1992) and Bmps can induce fibronectin expression and/or fibril assembly (Koli et al, 2004;Tang et al, 2003). Our data show that Tril is required for expression of sizzled, which controls fibronectin matrix deposition and thus Bmp responsiveness in the foregut of early Xenopus embryos (Kenny et al, 2012). It is also possible that Tril stimulates production of non-cell-autonomous signals required for mesoderm to form blood, independent of its effects of Bmp signaling.…”

Section: Discussionmentioning

confidence: 60%

Tril targets Smad7 for degradation to allow hematopoietic specification in Xenopus embryos

et al. 2016

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In Xenopus laevis, Bone morphogenetic proteins induce expression of the transcription factor Gata2 during gastrulation, and Gata2 is required in both ectodermal and mesodermal cells to enable mesoderm to commit to a hematopoietic fate. In the current studies, we identify tril as a Gata2 target gene that is required in both ectoderm and mesoderm for primitive hematopoiesis to occur. Tril is a transmembrane protein that functions as a co-receptor for Toll like receptors to mediate innate immune responses in the adult brain, but developmental roles for this molecule have not been identified. We show that Tril function is required both upstream and downstream of Bmp receptor mediated Smad1 phosphorylation for induction of Bmp target genes. Mechanistically, Tril triggers degradation of the Bmp inhibitor, Smad7. Tril-dependent down regulation of Smad7 relieves repression of endogenous Bmp signaling during gastrulation and this enables mesodermal progenitors to commit to a blood fate. Thus, Tril is a novel component of a Bmp-Gata2 positive feedback loop that plays an essential role in hematopoietic specification.

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“…HSPGs can also bind to BMP7 and either promote or inhibit signaling (45)(46)(47). Other ECM components or ECM-bound proteins, such as fibronectin, collagen, and members of the crossveinless family, promote BMP signaling through diverse and context-dependent mechanisms (48)(49)(50)(51)(52). The composition of the ECM varies between different tissues and cell types and thus it is feasible that the BMP4 prodomain might be required to facilitate interactions with obligate ECM binding partners present on ectodermal, but not mesodermal cells.…”

Section: Discussionmentioning

confidence: 99%

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Neugebauer¹,

Kwon

Kim³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.B one morphogenetic proteins (BMPs) are members of the TGFβ superfamily that were originally isolated as boneinducing morphogens and were subsequently found to play central roles during embryogenesis and in adult homeostasis (1). BMPs are clinically important therapeutic agents that are used to reverse bone loss caused by trauma, disease, and tumor resection (2). Their use as regenerative agents is limited, however, by their short half-life and low specific activity when implanted in vivo. Understanding how BMP activity is regulated is important for the development of more effective therapeutic agents for the treatment of bone injury and disease.BMPs bind to and activate a receptor complex consisting of type I and type II transmembrane serine/threonine kinases. Following ligand binding, activated receptors propagate their signal by phosphorylating one of the SMADs that is specific for the BMP pathway (SMAD1, -5, or -8). The phosphorylated Smads then form heterooligomers with the common Smad, Smad4, and this complex translocates into the nucleus where it binds to BMP response elements and activates transcription of target genes (1).BMPs are classified into subfamilies based on sequence homology. They signal as either homodimers, or as heterodimers from different subfamilies. For example, class I BMPs, which consist of BMP2 and BMP4, can heterodimerize with class II BMPs, consisting of BMP5-8 (3). Heterodimers composed of distinct BMP family members show a higher specific activity than do homodimers of either subunit. Homodimers of BMP2, -4, or -7, for example, can all induce bone formation, but heterodimers of BMP2 plus BMP7, or BMP4 plus BMP7 are significantly more potent (5-to 20-fold) than any of the homodimers in osteogenic differentiation assays (4-6). BMP2/7 and BMP4/7 heterodimers also sho...

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Sizzled-Tolloid Interactions Maintain Foregut Progenitors by Regulating Fibronectin-Dependent BMP Signaling

Cited by 20 publications

References 54 publications

Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs

Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs

Tril targets Smad7 for degradation to allow hematopoietic specification in Xenopus embryos

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

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