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At least 253 records · Page 14Linked to original sources
PubMed1998

Ventral mesoderm induction and patterning by bone morphogenetic protein heterodimers in Xenopus embryos.

Bone morphogenetic proteins (BMPs) perform diverse functions in vertebrate development. Here we demonstrate that the heterodimeric BMP-4/7 protein directly induces ventral mesoderm and blood in Xenopus animal caps, and BMP-2/7 heterodimers may function similarly. We also provide indirect evidence that BMP heterodimers function in embryos, using assays with dominant-negative BMP ligands. Homodimeric BMP-2 and BMP-4 proteins do not induce mesoderm, but they ventralize mesoderm induction by activin. In contrast, BMP-7 protein interferes with mesoderm induction by activin, but BMP-7 stimulates ventral mesoderm induction by the heterodimer, BMP-4/7. This novel property of BMP-7 distinguishes it from other BMPs. BMP-7 may therefore function in early embryogenesis to antagonize activin signals and potentiate BMP signals. We propose that BMP heterodimers convey signals for ventral mesoderm induction and patterning in Xenopus development.

Activins↗
PubMed1997

Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas.

The generation of the pancreas and small intestine from the embryonic gut depends on intercellular signalling between the endodermal and mesodermal cells of the gut. In particular, the differentiation of intestinal mesoderm into smooth muscle has been suggested to depend on signals from adjacent endodermal cells. One candidate mediator of endodermally derived signals in the embryonic hindgut is the secreted protein Sonic hedgehog (Shh). The Shh gene is expressed throughout the embryonic gut endoderm with the exception of the pancreatic bud endoderm, which instead expresses high levels of the homeodomain protein Ipf1/Pdx1 (insulin promoter factor 1/pancreatic and duodenal homeobox 1), an essential regulator of early pancreatic development. Here, we have examined whether the differential expression of Shh in the embryonic gut tube controls the differentiation of the surrounding mesoderm into specialised mesoderm derivatives of the small intestine and pancreas. To test this, we used the promoter of the Ipf1/Pdx1 gene to selectively express Shh in the developing pancreatic epithelium. In Ipf1/Pdx1-Shh transgenic mice, the pancreatic mesoderm developed into smooth muscle and interstitial cells of Cajal, characteristic of the intestine, rather than into pancreatic mesenchyme and spleen. Also, pancreatic explants exposed to Shh underwent a similar program of intestinal differentiation. These results provide evidence that the differential expression of endodermally derived Shh controls the fate of adjacent mesoderm at different regions of the gut tube.

Animals↗
PubMed1995

Mesoderm formation in response to Brachyury requires FGF signalling.

BACKGROUND: The Brachyury (T) gene is required for the formation of posterior mesoderm and for axial development in both mouse and zebrafish embryos. In these species, and in Xenopus, the gene is expressed transiently throughout the presumptive mesoderm, and transcripts then persiste in notochord and posterior tissues. In Xenopus embryos, expression of the Xenopus homologue of Brachyury, Xbra, can be induced in presumptive ectoderm by basic fibroblast growth factor (FGF) and activin; in the absence of functional FGF or activin signalling pathways, expression of the gene is severely reduced. Ectopic expression of Xbra in presumptive ectoderm causes mesoderm to be formed. As Brachyury and its homologues encode sequence-specific DNA-binding proteins, it is likely that each functions by directly activating downstream mesoderm-specific genes. RESULTS: We show that expression in Xenopus embryos of RNA encoding a dominant-negative FGF receptor inhibits the mesoderm-inducing activity of Xbra. We demonstrate that ectopic expression of Xbra activates transcription of the embryonic FGF gene, and that embryonic FGF can induce expression of Xbra. This suggests that the two genes are components of a regulatory loop. Consistent with this idea, dissociation of Xbra-expressing cells causes a dramatic and rapid reduction in levels of Xbra, but the reduction can be inhibited by addition of FGF. CONCLUSION: Formation of mesoderm tissue requires an intact FGF signalling pathway downstream of Brachyury. This requirement is due to a regulatory loop, in which Brachyury activates expression of a member of the FGF family, and FGF maintains expression of Brachyury.(ABSTRACT TRUNCATED AT 250 WORDS)

Activins↗
PubMed1992

Involvement of p21ras in Xenopus mesoderm induction.

During early vertebrate embryogenesis, mesoderm is specified by a signal emanating from prospective endoderm. This signal can respecify Xenopus prospective ectoderm as mesoderm, and can be mimicked by members of the fibroblast growth factor and transforming growth factor-beta families. In other systems, the p21c-ras proto-oncogene product has been implicated in signal transduction for various polypeptide growth factors. We report here that a dominant inhibitory ras mutant blocks the mesoderm-inducing activity of fibroblast growth factor and activin, as well as the endogenous inducing activity of prospective endoderm. A constitutively active ras mutant partially mimics these activities. These results indicate that p21ras may have a central role in the transduction of the mesoderm inductive signal. Basic fibroblast growth factor and activin have emerged as candidates for endogenous mesoderm-inducing molecules. The character of the mesoderm induced by these two factors is overlapping but distinct when assessed both by histological and molecular criteria. The signal transduction pathways used during induction by these factors are unknown. We used messenger RNA microinjection of Xenopus eggs to express a dominant inhibitory mutant ras, p21(Asn 17)Ha-ras, in cells competent to respond to inducing factors to examine the role of p21ras in this response. This mutant, which has a reduced affinity for GTP relative to GDP, blocks a variety of mitogenic signals in 3T3 fibroblasts as well as the differentiation of pheochromocytoma cells in response to nerve growth factor.

Activins↗
PubMed1992

Ectopic mesoderm formation in Xenopus embryos caused by widespread expression of a Brachyury homologue.

The Brachyrury (T) gene is required cell-autonomously for mesoderm formation in the posterior of the mouse embryo, and both is complementary DNA sequence and expression pattern closely resemble those of a Xenopus homologue (Xbra), suggesting that these genes have an evolutionarily conserved function in vertebrate development. Strong expression of Xbra messenger RNA is found in the ring of involuting mesoderm during Xenopus gastrulation, and the expression of Xbra is an immediate-early response of animal pole blastomeres to mesoderm-inducing factors. To assess the role of Xbra in mesoderm formation, we increased its domain of expression in the embryo by microinjection of Xbra transcripts into the animal pole of Xenopus embryos at the one-cell stage. We show that expression of Xbra by cells of the early embryo is sufficient to direct their development into differentiated mesodermal tissues. At the molecular level this response shows a sharp threshold of sensitivity to the dose of Xbra RNA delivered, and we suggest that Xbra may act as a genetic switch initiating posterior mesodermal specification during embryogenesis.

Animals↗
PubMedDate not supplied

dpp induces mesodermal gene expression in Drosophila.

Inductive interactions between germ layers are an essential feature of the development of many organisms. In several species these interactions are mediated by members of the transforming growth factor-beta (TGF beta) family. In amphibians, different concentrations of activin can induce different types of mesoderm in the animal cap assay. In Drosophila, a member of the TGF beta family, decapentaplegic (dpp), acts as an inductive signal. Midway through embryogenesis, dpp is expressed in the visceral mesoderm, and enhances the expression of the homeotic gene labial in the underlying midgut endoderm. Earlier in development, however, dpp expression is limited to the dorsal ectoderm. At this stage in development, thickveins, a dpp receptor, is expressed in the mesoderm, and this suggests that ectodermal dpp might not only be required for development of dorsal ectoderm, but could also act inductively to mediate pattern formation in the underlying mesoderm. Here we show, by expressing dpp ectopically in the ectoderm and mesoderm and by examining dpp null mutant embryos, that dpp regulates expression of mesodermal genes.

Animals↗
PubMed1997

Expressions of PDGF receptor alpha, c-Kit and Flk1 genes clustering in mouse chromosome 5 define distinct subsets of nascent mesodermal cells.

In gastrulating embryos, various types of cells are generated before differentiation into specific lineages. The mesoderm of the gastrulating mouse embryo represents a group of such intermediate cells. PDGF receptor alpha (PDGFRalpha), c-Kit and fetal liver kinase 1 (Flk1) are expressed in distinctive mesodermal derivatives of post-gastrulation embryos. Their expressions during gastrulation were examined by whole mount immunostaining with monoclonal antibodies against these three receptors. The antibodies stained different mesodermal subsets in gastrulating embryos. Flow cytometry of head fold stage embryos revealed that Flk1+ mesodermal cells could be further classified by the level of c-Kit expression. To examine the possibility that hematopoietic cell differentiation is initiated from the Flk1+ mesoderm, embryonic stem (ES) cells were cultured on the OP9 or PA6 stromal cell layer; the former but not the latter supported in vitro hematopoiesis from ES cells. Flk1+ cells were detected only on the OP9 cell layer from day 3 of differentiation before the appearance of hematopoietic cells. Thus, Flk1+ cells will be required for in vitro ES cell differentiation into hematopoietic cells. The results suggest that these three receptor tyrosine kinases will be useful for defining and sorting subsets of mesodermal cells from embryos or in vitro cultured ES cells.

Animals↗
PubMed2001

Comparative study of sequential expression of the organizer-related genes in normal Cynops pyrrhogaster embryos and mesodermalized ectoderm.

An artificially mesodermalized ectoderm (mE) of early Cynops pyrrhogaster gastrula acquires the organizer property; the mE is able to induce the secondary axis. The expression of organizer-related genes was investigated during the mesodermalizing process of the mE. The expression of C. pyrrhogaster organizer-related genes, such as bra, gsc, lim-1, chd and noggin, were analyzed. Cynops pyrrhogaster shh expression was also investigated. The organizer-related genes were activated by 12 h after the mesoderm-inducing stimulus. It was noted that there was a temporal gap in the expression of each gene. The expression of bra and gsc seemed to be more quickly activated during the mesodermalizing process. While expression of lim-1 and noggin was activated later than that of bra and gsc, lim-1 expression was earlier than chd and noggin expression. Shh expression was activated later than lim-1/noggin. The present study suggests the possibility that the bra/gsc, lim-1, chd, noggin and shh genes are expressed one by one in that order during the mesodermalizing of the presumptive ectoderm. It also indicates that the sequence is not always consistent with that of the whole embryo during normal embryogenesis. The meaning of the discrepancy will be discussed in connection with the cascade of certain genes expressed during the mesodermalizing process.

Actins↗
PubMed1996

Identification of novel genes in Drosophila reveals the complex regulation of early gene activity in the mesoderm.

Two zygotic genes, twist and snail, are indispensable for the correct establishment of the mesoderm primordium in the early Drosophila embryo. They are also needed for morphogenesis and differentiation of the mesoderm. Both genes code for transcription factors with different, albeit complementary, functions. Therefore, to understand the early development of the mesoderm, it will be necessary to identify and study the genes regulated by twist and snail. We have searched for downstream genes using a subtractive cDNA library enriched in sequences expressed in the mesoderm. We have isolated sequences that correspond to 13 novel early mesoderm genes. These novel genes show a variety of expression patterns and also differ in their dependence on twist and snail functions. This indicates that the regulation of early gene activity in the mesoderm is more complex than previously thought.

Animals↗
PubMed1997

Twist-mediated activation of the NK-4 homeobox gene in the visceral mesoderm of Drosophila requires two distinct clusters of E-box regulatory elements.

NK-4, also called msh2 and tinman, encodes a homeodomain transcription factor that is required for the development of the dorsal mesoderm and its derivatives in the Drosophila embryo. Genetic analyses indicate that NK-4 resides downstream of the mesodermal determinant twist, which encodes a basic helix-loop-helix-type transcription factor. However, the regulation of NK-4 by twist remains poorly understood. Using expression assays in cultured cells and transgenic flies, we show that two distinct clusters of E-box regulatory sequences, present upstream of the NK-4 gene, mediate NK-4 expression in the visceral mesoderm. These elements are conserved between the Drosophila melanogaster and Drosophila virilis NK-4 genes and serve as binding sites for Twist (E1 cluster) and NK-4 (E2 cluster) proteins. In cultured cells, Twist and NK-4 binding results in activation of NK-4 gene expression. In transgenic animals, the E1 and E2 clusters are functionally connected, and both elements are required for NK-4 activation in cells of the visceral mesoderm and also for NK-4 repression in cells of the somatic musculature. These results demonstrate that NK-4 is a direct transcriptional target for Twist and its own gene product in visceral mesodermal cells, supporting the idea that twist and NK-4 function in the subdivision of the mesoderm during Drosophila embryogenesis.

Animals↗
PubMed2002

The molecular basis of Src kinase specificity during vertebrate mesoderm formation.

Members of the Src family of non-receptor tyrosine kinases play a critical role in mesoderm formation in the frog, Xenopus laevis, acting as required mediators downstream of the fibroblast growth factor receptor. At least four members of this gene family, Src, Fyn, Yes, and Laloo, are expressed during early embryonic development. Ectopic expression of Laloo and Fyn, but not Src, induce mesoderm in ectodermal explants, indicating that these factors are non-redundant during early vertebrate development. Here we investigate the basis for the differential activity of the Src and Laloo kinases during mesoderm formation. We demonstrate that although both Src and Laloo physically interact with the substrate protein SNT-1/FRS2alpha only Laloo phosphorylates SNT-1, an event previously shown to be required for the activity of the latter and for mesoderm induction in vivo. We show that Src is enzymatically capable of stimulating mesoderm formation, as an activated Src construct both phosphorylates SNT-1 and induces mesoderm in explant cultures. However, a chimeric Laloo construct containing a Src C-terminal tail is inactive, suggesting that the early embryo contains a specific Laloo-activating, or Src-inactivating, factor. Finally, through further chimeric analysis, we provide evidence to suggest that differences in Laloo and Src activity are also mediated by the SH2, SH3, and kinase domains of these molecules.

Animals↗
PubMed2006

FoxD3 and Grg4 physically interact to repress transcription and induce mesoderm in Xenopus.

FoxD3 is a forkhead-related transcriptional regulator that is essential for multiple developmental processes in the vertebrate embryo, including neural crest development and maintenance of mammalian stem cell lineages. Recent results demonstrate a requirement for FoxD3 in Xenopus mesodermal development. In the gastrula, FoxD3 functions as a transcriptional repressor in the Spemann organizer to maintain the expression of Nodal-related members of the transforming growth factor-beta superfamily that induce dorsal mesoderm formation. Here we report that the function of FoxD3 in mesoderm induction is dependent on the recruitment of transcriptional corepressors of the TLE/Groucho family. Structure-function analyses indicate that the transcriptional repression and mesoderm induction activities of FoxD3 are dependent on a C-terminal domain, as well as specific DNA-binding activity conferred by the forkhead domain. The C-terminal domain contains a heptapeptide similar to the eh1/GEH Groucho interaction motif. Deletion and point mutagenesis demonstrated that the FoxD3 eh1/GEH motif is required for both repression of transcription and induction of mesoderm, as well as the direct physical interaction of FoxD3 and Grg4 (Groucho-related gene-4). Consistent with a functional interaction of FoxD3 and Grg4, the transcriptional repression activity of FoxD3 is enhanced by Grg4, and reduced by Grg5, a dominant inhibitory Groucho protein. The results indicate that FoxD3 recruitment of Groucho corepressors is essential for the transcriptional repression of target genes and induction of mesoderm in Xenopus.

Amino Acid Motifs↗
PubMed1997

The mesodermal expression of rolling stone (rost) is essential for myoblast fusion in Drosophila and encodes a potential transmembrane protein.

In homozygous rolling stone embryos, the fusion of myoblasts to syncytial myotubes is diminished. Nevertheless, the visceral mesoderm, the heart mesoderm, and few somatic muscles are properly formed. Thus, we postulate a central role of rolling stone for the fusion process within the somatic mesoderm. We have cloned the rolling stone gene, and the deduced protein sequence is in accordance with a transmembrane protein, which agrees with the enrichment of Rost in the membrane fraction of Drosophila embryos. No homologous genes have been described so far. rolling stone is expressed in the embryonic nervous system and cells of the somatic mesoderm, most notable in muscle founder cells. To elucidate the function of rolling stone for myoblast fusion, we applied a knock-out strategy. The expression of an antisense rolling stone transcript specifically within the mesoderm of wild-type embryos results in fusion defects of myoblasts, proving that the rolling stone expression in the mesoderm is responsible for the rolling stone phenotype. We suggest that rolling stone is a member of a group of genes that are necessary for the fusion process during myogenesis.

Amino Acid Sequence↗
PubMed1969

The differential sensitivity of cultured chick mesodermal cells to actinomycin D.

Cells were isolated from the somite mesoderm and from the unsegmented (presomite) mesoderm of early chick embryos and exposed to actinomycin D in single cell culture. Actinomycin D inhibited proliferation in cell cultures derived from the unsegmented mesoderm, although the same concentrations of this antibiotic did not inhibit cultures derived from the somite mesoderm. This differential sensitivity parallels the regionally specific necrosis and degeneration observed in the unsegmented mesoderm of intact chick embryos exposed to actinomycin D. In culture, both cell types exhibited approximately the same permeability to labeled actinomycin D and showed comparable inhibition of RNA, DNA, and protein syntheses in the presence of the antibiotic. However, freshly isolated mesodermal cells from the somite region had a higher content of RNA than did cells from the unsegmented region, and the somite cells maintained a higher rate of macromolecular synthesis in untreated cultures.

Animals↗
PubMed2003

A role for maternal beta-catenin in early mesoderm induction in Xenopus.

Mesoderm formation results from an inducing process that requires maternal and zygotic FGF/MAPK and TGFbeta activities, while maternal activation of the Wnt/beta-catenin pathway determines the anterior-dorsal axis. Here, we show a new role of Wnt/beta-catenin signaling in mesoderm induction. We find that maternal beta-catenin signaling is not only active dorsally but also all around the equatorial region, coinciding with the prospective mesoderm. Maternal beta-catenin function is required both for expression of dorsal genes and for activation of MAPK and the mesodermal markers Xbra and eomesodermin. beta-catenin acts in a non- cell-autonomous manner upstream of zygotic FGF and nodal signals. The Wnt/beta-catenin activity in the equatorial region of the early embryo is the first example of a maternally provided mesoderm inducer restricted to the prospective mesoderm.

Animals↗
PubMed1990

Mesoderm induction by fibroblast growth factor in early Xenopus development.

In early amphibian development the mesoderm is formed around the equator of the blastula in response to inductive signals from the endoderm. At the time of its formation the mesoderm consists of a large 'ventral type' zone and a small 'organizer' zone. A screen of candidate substances showed that a small group of heparin binding growth factors (HBGFs) were active as mesoderm inducing agents in vitro. The fibroblast growth factors (aFGF and bFGF) and embryonal carcinoma derived growth factor (ECDGF) all show similar potency and can produce ventral inductions at concentrations above about 100 pm. Single blastula ectoderm cells can be induced and will differentiate in a defined medium to form mesodermal tissues and all inner blastula cells are competent to respond to the factors. Inducing activity can be extracted from Xenopus blastulae and can be purified by heparin affinity chromatography. Antibody neutralization and Western blotting experiments identify this activity as bFGF. The amounts present are small but would be sufficient to evoke ventral inductions in vivo. It is not yet known whether the bFGF is localized to the endoderm, although it is known that inducing activity secreted by endodermal cells can be neutralized by heparin. The competence of ectoderm to respond to FGF rises from about the 128-cell-stage and falls again by the onset of gastrulation. This change is paralleled by a rise and fall of binding of 125I-labelled aFGF. Chemical cross-linking reveals that this binding is attributable to a receptor of molecular mass about 130 kilodaltons (kDa). The receptor is present both in the marginal zone, which responds to the signal in vivo, and in the animal pole region, which is not induced in vivo but which will respond to HBGFs in vitro. In intact embryos we believe that the ventral type mesoderm forms the somites, kidney and other intermediate structures as well as the blood islands of the ventral midline. These intermediate structures are induced as a function of distance from the organizer in a process called 'dorsalization'. Lithium salts have a dorsalizing effect on whole embryos and also on explants from the ventral marginal zone, causing them to form large blocks of muscle. Lithium will also cause large muscle blocks to form when applied to ectoderm explants together with FGF. It is difficult to extend these results directly to mammalian embryos, but we have shown that the products of the murine int-2 gene and of the human k-fgf genes are active as mesoderm inducing factors.

Animals↗
PubMed1998

Smad proteins act in combination with synergistic and antagonistic regulators to target Dpp responses to the Drosophila mesoderm.

Dorsal mesoderm induction in arthropods and ventral mesoderm induction in vertebrates are closely related processes that involve signals of the BMP family. In Drosophila, induction of visceral mesoderm, dorsal muscles, and the heart by Dpp is, at least in part, effected through the transcriptional activation and function of the homeobox gene tinman in dorsal mesodermal cells during early embryogenesis. Here we present a functional dissection of a tinman enhancer that mediates the Dpp response. We provide evidence that mesoderm-specific induction of tinman requires the binding of both activators and repressors. Screens for binding factors yielded Tinman itself and the Smad4 homolog Medea. We show that the binding and synergistic activities of Smad and Tinman proteins are critical for mesodermal tinman induction, whereas repressor binding sites prevent induction in the dorsal ectoderm and amnioserosa. Thus, integration of positive and negative regulators on enhancers of target genes appears to be an important mechanism in tissue-specific induction by TGF-beta molecules.

Amino Acid Sequence↗
PubMed1998

Combinatorial signaling codes for the progressive determination of cell fates in the Drosophila embryonic mesoderm.

Mesodermal progenitors arise in the Drosophila embryo from discrete clusters of lethal of scute (l'sc)-expressing cells. Using both genetic loss-of-function and targeted ectopic expression approaches, we demonstrate here that individual progenitors are specified by the sequential deployment of unique combinations of intercellular signals. Initially, the intersection between the Wingless (Wg) and Decapentaplegic (Dpp) expression domains demarcate an ectodermal prepattern that is imprinted on the adjacent mesoderm in the form of a L'sc precluster. All mesodermal cells within this precluster are competent to respond to a subsequent instructive signal mediated by two receptor tyrosine kinases (RTKs), the Drosophila epidermal growth factor receptor (DER) and the Heartless (Htl) fibroblast growth factor receptor. By monitoring the expression of the diphosphorylated form of mitogen-associated protein kinase (MAPK), we found that these RTKs are activated in small clusters of cells within the original competence domain. Each cluster represents an equivalence group because all members initially resemble progenitors in their expression of both L'sc and mesodermal identity genes. Thus, localized RTK activity induces the formation of mesodermal equivalence groups. The RTKs remain active in the single progenitor that emerges from each cluster under the subsequent inhibitory influence of the neurogenic genes. Moreover, DER and Htl are differentially involved in the specification of particular progenitors. We conclude that distinct cellular identity codes are generated by the combinatorial activities of Wg, Dpp, EGF, and FGF signals in the progressive determination of embryonic mesodermal cells.

Animals↗