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PubMed1991

Retinoic acid perturbs the expression of Xhox.lab genes and alters mesodermal determination in Xenopus laevis.

Retinoic acid (RA) treatment of Xenopus laevis embryos leads to anterior truncation of the body axis (Durston et al. 1989; Sive et al. 1990). These initial studies suggested that RA may play a role in the patterning of the primary body axis. At least one target of RA was shown previously to be dorsal ectoderm. In this report we extend this observation and also ask whether RA alters the determination and inducing capacity of mesodermal tissue. To facilitate this analysis we isolated the homeo-domain-containing genes Xhox.lab1 and Xhox.lab2. These genes were expressed in both ectoderm and mesoderm during the RA-sensitive period and were strongly induced by RA in both germ layers. In particular, anterior regions expressed low levels of Xhox.lab RNAs in untreated embryos but showed increased expression after RA application. We show further that although RA-treated embryos contained anterior-inducing mesoderm, the amount of this activity appeared to be lower than that of controls. Additionally, we document that RA suppressed lateral (muscle) and ventral (blood) mesoderm differentiation. The data indicate that RA alters mesodermal determination and causes axial perturbation both by depressing the ability of dorsal mesoderm to induce anterior structures and by altering the response of dorsal ectoderm to induction. These analyses suggest that Xhox.lab genes may be responsible, in part, for mediating the RA effect.

Amino Acid Sequence↗
PubMed1991

twist and snail as positive and negative regulators during Drosophila mesoderm development.

twist and snail are members of the helix-loop-helix and zinc-finger protein families, respectively, and determine the development of the mesoderm in Drosophila. This paper analyzes their role in mesoderm development by examining how they affect the expression of downstream genes. twist and snail act by regulating gene expression in the mesoderm and in neighboring regions, and have distinct roles in this process. snail prevents expression in the mesoderm of genes that are destined to be active only in more lateral or dorsal regions. twist is required for the activation of downstream mesodermal genes. twist is also required for the full expression of snail and for the maintenance of its own expression. Only the absence of both twist and snail results in the complete loss of all mesodermal characteristics.

Animals↗
PubMed2000

The bHLH regulator pMesogenin1 is required for maturation and segmentation of paraxial mesoderm.

Paraxial mesoderm in vertebrates gives rise to all trunk and limb skeletal muscles, the trunk skeleton, and portions of the trunk dermis and vasculature. We show here that germline deletion of mouse pMesogenin1, a bHLH class gene specifically expressed in developmentally immature unsegmented paraxial mesoderm, causes complete failure of somite formation and segmentation of the body trunk and tail. At the molecular level, the phenotype features dramatic loss of expression within the presomitic mesoderm of Notch/Delta pathway components and oscillating somitic clock genes that are thought to control segmentation and somitogenesis. Subsequent patterning and specification steps for paraxial mesoderm also fail, leading to a complete absence of all trunk paraxial mesoderm derivatives, which include skeletal muscle, vertebrae, and ribs. We infer that pMesogenin1 is an essential upstream regulator of trunk paraxial mesoderm development and segmentation.

Abnormalities, Multiple↗
PubMed2001

Inhibition of Wnt activity induces heart formation from posterior mesoderm.

In the chick, heart mesoderm is induced by signals from the anterior endoderm. Although BMP-2 is expressed in the anterior endoderm, BMP activity is necessary but not sufficient for heart formation. Previous work from our lab has suggested that one or more additional factors from anterior endoderm are required. Crescent is a Frizzled-related protein that inhibits Wnt-8c and is expressed in anterior endoderm during gastrulation. At the same stages, expression of Wnt-3a and Wnt-8c is restricted to the primitive streak and posterior lateral plate, and is absent from the anterior region where crescent is expressed. Posterior lateral plate mesoderm normally forms blood, but coculture of this tissue with anterior endoderm or infection with RCAS-crescent induces formation of beating heart muscle and represses formation of blood. Dkk-1, a Wnt inhibitor of a different protein family, similarly induces heart-specific gene expression in posterior lateral plate mesoderm. Furthermore, we have found that ectopic Wnt signals can repress heart formation from anterior mesoderm in vitro and in vivo and that forced expression of either Wnt-3a or Wnt-8c can promote development of primitive erythrocytes from the precardiac region. We conclude that inhibition of Wnt signaling promotes heart formation in the anterior lateral mesoderm, whereas active Wnt signaling in the posterior lateral mesoderm promotes blood development. We propose a model in which two orthogonal gradients, one of Wnt activity along the anterior-posterior axis and the other of BMP signals along the dorsal-ventral axis, intersect in the heart-forming region to induce cardiogenesis in a region of high BMP and low Wnt activity.

Animals↗
PubMed1993

The expression pattern of the chicken homeobox-containing gene GHox-7 in developing polydactylous limb buds suggests its involvement in apical ectodermal ridge-directed outgrowth of limb mesoderm and in programmed cell death.

The limb buds of the polydactylous mutant embryos, talpid2 and diplopodia-5, possess expanded distal apexes surmounted by prolongated thickened apical ectodermal ridges that promote the outgrowth and formation of digits from both the anterior and posterior mesoderm of the mutant limb buds. The chicken homeobox-containing gene GHox-7 exhibits an expanded domain of expression throughout the expanded subridge mesoderm of the mutant limb buds, providing support for the hypothesis that GHox-7 expression by subridge mesenchymal cells is involved in the outgrowth-promoting effect of the apical ectodermal ridge. During normal limb development GHox-7 is also expressed by the mesoderm in the proximal anterior nonchondrogenic periphery of the limb bud, which includes, but is not limited to the anterior necrotic zone. GHox-7 is also expressed in the posterior necrotic zone at the mid-proximal posterior edge of the limb bud. In contrast, GHox-7 is not expressed in either the proximal anterior or posterior peripheral mesoderm of talpid2 and diplopodia-5 limb buds which lack proximal anterior and posterior necrotic zones. Furthermore, retinoic acid-coated bead implants, which diminish cell death in the anterior necrotic zone, elicit a local inhibition of GHox-7 expression in the proximal anterior peripheral mesoderm. These results support the suggestion that GHox-7 may be involved in defining regions of programmed cell death during limb development. Furthermore, these studies indicate that the distal subridge and proximal anterior nonchondrogenic mesodermal domains of GHox-7 expression are independently regulated.

Animals↗
PubMed2003

Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation.

The hematopoietic and endothelial lineages derive from mesoderm and are thought to develop through the maturation of a common progenitor, the hemangioblast. To investigate the developmental processes that regulate mesoderm induction and specification to the hemangioblast, we generated an embryonic stem cell line with the green fluorescent protein (GFP) targeted to the mesodermal gene, brachyury. After the in vitro differentiation of these embryonic stem cells to embryoid bodies, developing mesodermal progenitors could be separated from those with neuroectoderm potential based on GFP expression. Co-expression of GFP with the receptor tyrosine kinase Flk1 revealed the emergence of three distinct cell populations, GFP(-)Flk1(-), GFP(+)Flk1(-) and GFP(+)Flk1(+) cells, which represent a developmental progression ranging from pre-mesoderm to prehemangioblast mesoderm to the hemangioblast.

Animals↗
PubMed2003

Lmo2 and Scl/Tal1 convert non-axial mesoderm into haemangioblasts which differentiate into endothelial cells in the absence of Gata1.

The LIM domain protein Lmo2 and the basic helix-loop-helix transcription factor Scl/Tal1 are expressed in early haematopoietic and endothelial progenitors and interact with each other in haematopoietic cells. While loss-of-function studies have shown that Lmo2 and Scl/Tal1 are essential for haematopoiesis and angiogenic remodelling of the vasculature, gain-of-function studies have suggested an earlier role for Scl/Tal1 in the specification of haemangioblasts, putative bipotential precursors of blood and endothelium. In zebrafish embryos, Scl/Tal1 can induce these progenitors from early mesoderm mainly at the expense of the somitic paraxial mesoderm. We show that this restriction to the somitic paraxial mesoderm correlates well with the ability of Scl/Tal1 to induce ectopic expression of its interaction partner Lmo2. Co-injection of lmo2 mRNA with scl/tal1 dramatically extends its effect to head, heart, pronephros and pronephric duct mesoderm inducing early blood and endothelial genes all along the anteroposterior axis. Erythroid development, however, is expanded only into pronephric mesoderm, remaining excluded from head, heart and somitic paraxial mesoderm territories. This restriction correlates well with activation of gata1 transcription and co-injection of gata1 mRNA along with scl/tal1 and lmo2 induces erythropoiesis more broadly without ventralising or posteriorising the embryo. While no ectopic myeloid development from the Scl/Tal1-Lmo2-induced haemangioblasts was observed, a dramatic increase in the number of endothelial cells was found. These results suggest that, in the absence of inducers of erythroid or myeloid haematopoiesis, Scl/Tal1-Lmo2-induced haemangioblasts differentiate into endothelial cells.

Animals↗
PubMed2004

Investigating the origins of triploblasty: 'mesodermal' gene expression in a diploblastic animal, the sea anemone Nematostella vectensis (phylum, Cnidaria; class, Anthozoa).

Mesoderm played a crucial role in the radiation of the triploblastic Bilateria, permitting the evolution of larger and more complex body plans than in the diploblastic, non-bilaterian animals. The sea anemone Nematostella is a non-bilaterian animal, a member of the phylum Cnidaria. The phylum Cnidaria (sea anemones, corals, hydras and jellyfish) is the likely sister group of the triploblastic Bilateria. Cnidarians are generally regarded as diploblastic animals, possessing endoderm and ectoderm, but lacking mesoderm. To investigate the origin of triploblasty, we studied the developmental expression of seven genes from Nematostella whose bilaterian homologs are implicated in mesodermal specification and the differentiation of mesodermal cell types (twist, snailA, snailB, forkhead, mef2, a GATA transcription factor and a LIM transcription factor). Except for mef2, the expression of these genes is largely restricted to the endodermal layer, the gastrodermis. mef2 is restricted to the ectoderm. The temporal and spatial expression of these 'mesoderm' genes suggests that they may play a role in germ layer specification. Furthermore, the predominantly endodermal expression of these genes reinforces the hypothesis that the mesoderm and endoderm of triploblastic animals could be derived from the endoderm of a diploblastic ancestor. Alternatively, we consider the possibility that the diploblastic condition of cnidarians is a secondary simplification, derived from an ancestral condition of triploblasty.

Amino Acid Sequence↗
PubMed2005

Transgenic zebrafish reveal stage-specific roles for Bmp signaling in ventral and posterior mesoderm development.

Bone morphogenetic protein (Bmp) signaling is crucial for the formation and patterning of zebrafish ventral and posterior mesoderm. Mutants defective in the Bmp pathway have expanded trunk muscle, abnormal tails and severely impaired development of ventral mesodermal derivatives such as vasculature, blood and pronephros. As Bmps continue to be expressed in the ventral and posterior mesoderm after gastrulation, it is likely that Bmp signaling continues to play an important developmental role during outgrowth of the posterior body. However, because Bmp signaling plays an essential role during the gastrula stages, it has not been possible with mutants or standard disruption techniques to determine the later functions of the Bmp pathway. To study the role of Bmp signaling in the ventral and posterior mesoderm during trunk and tail outgrowth, we generated a transgenic zebrafish line containing a heatshock-inducible dominant-negative Bmp receptor-GFP fusion. Our data show that Bmps are important for tail organizer formation and for patterning the ventral mesoderm during early gastrulation. However, from mid-gastrulation to the early somitogenesis stages, Bmp signaling is important for ventral tail fin development and for preventing secondary tail formation. We conclude that the role of Bmp signaling in the ventral and posterior mesoderm changes as gastrulation proceeds.

Animals↗
PubMed2005

Gata4 expression in lateral mesoderm is downstream of BMP4 and is activated directly by Forkhead and GATA transcription factors through a distal enhancer element.

The GATA family of zinc-finger transcription factors plays key roles in the specification and differentiation of multiple cell types during development. GATA4 is an early regulator of gene expression during the development of endoderm and mesoderm, and genetic studies in mice have demonstrated that GATA4 is required for embryonic development. Despite the importance of GATA4 in tissue specification and differentiation, the mechanisms by which Gata4 expression is activated and the transcription factor pathways upstream of GATA4 remain largely undefined. To identify transcriptional regulators of Gata4 in the mouse, we screened conserved noncoding sequences from the mouse Gata4 gene for enhancer activity in transgenic embryos. Here, we define the regulation of a distal enhancer element from Gata4 that is sufficient to direct expression throughout the lateral mesoderm, beginning at 7.5 days of mouse embryonic development. The activity of this enhancer is initially broad but eventually becomes restricted to the mesenchyme surrounding the liver. We demonstrate that the function of this enhancer in transgenic embryos is dependent upon highly conserved Forkhead and GATA transcription factor binding sites, which are bound by FOXF1 and GATA4, respectively. Furthermore, the activity of the Gata4 lateral mesoderm enhancer is attenuated by the BMP antagonist Noggin, and the enhancer is not activated in Bmp4-null embryos. Thus, these studies establish that Gata4 is a direct transcriptional target of Forkhead and GATA transcription factors in the lateral mesoderm, and demonstrate that Gata4 lateral mesoderm enhancer activation requires BMP4, supporting a model in which GATA4 serves as a downstream effector of BMP signaling in the lateral mesoderm.

Animals↗
PubMed2006

Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development.

The development of the segmented pharyngeal apparatus involves complex interaction of tissues derived from all three germ layers. The role of mesoderm is the least studied, perhaps because of its apparent lack of anatomical boundaries and positionally restricted gene expression. Here, we report that the mesoderm-specific deletion of Tbx1, a T-box transcription factor, caused severe pharyngeal patterning and cardiovascular defects, while mesoderm-specific restoration of Tbx1 expression in a mutant background corrected most of those defects in the mouse. We show that some organs, e.g. the thymus, require Tbx1 expression in the mesoderm and in the epithelia. In addition, these experiments revealed that different pharyngeal arches require Tbx1 in different tissues. Finally, we show that Tbx1 in the mesoderm is required to sustain cell proliferation. Thus, the mesodermal transcription program is not only crucial for cardiovascular development, but is also key in the development and patterning of pharyngeal endoderm.

Animals↗
PubMed2006

BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites.

Bmpr1a encodes the BMP type IA receptor for bone morphogenetic proteins (BMPs), including 2 and 4. Here, we use mosaic inactivation of Bmpr1a in the epiblast of the mouse embryo (Bmpr-MORE embryos) to assess functions of this gene in mesoderm development. Unlike Bmpr1a-null embryos, which fail to gastrulate, Bmpr-MORE embryos initiate gastrulation, but the recruitment of prospective paraxial mesoderm cells to the primitive streak is delayed. This delay causes a more proximal distribution of cells with paraxial mesoderm character within the primitive streak, resulting in a lateral expansion of somitic mesoderm to form multiple columns. Inhibition of FGF signaling restores the normal timing of recruitment of prospective paraxial mesoderm and partially rescues the development of somites. This suggests that BMP and FGF signaling function antagonistically during paraxial mesoderm development.

Animals↗
PubMed2006

Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo.

Studies in Caenorhabditis elegans and vertebrates have established that the MAP kinase-related protein NLK counteracts Wnt signalling by downregulating the transcription factor TCF. Here, we present evidence that during early development of the sea urchin embryo, NLK is expressed in the mesodermal precursors in response to Notch signalling and directs their fate by downregulating TCF. The expression pattern of nlk is strikingly similar to that of Delta and the two genes regulate the expression of each other. nlk overexpression, like ectopic activation of Notch signalling, provoked massive formation of mesoderm and associated epithelial mesenchymal transition. NLK function was found to be redundant with that of the MAP kinase ERK during mesoderm formation and to require the activity of the activating kinase TAK1. In addition, the sea urchin NLK, like its vertebrate counterpart, antagonizes the activity of the transcription factor TCF. Finally, activating the expression of a TCF-VP16 construct at blastula stages strongly inhibits endoderm and mesoderm formation, indicating that while TCF activity is required early for launching the endomesoderm gene regulatory network, it has to be downregulated at blastula stage in the mesodermal lineage. Taken together, our results indicate that the evolutionarily conserved TAK/NLK regulatory pathway has been recruited downstream of the Notch/Delta pathway in the sea urchin to switch off TCF-beta-catenin signalling in the mesodermal territory, allowing precursors of this germ layer to segregate from the endomesoderm.

Amino Acid Sequence↗
PubMed2006

Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle.

Recent experiments, showing that both cranial paraxial and splanchnic mesoderm contribute to branchiomeric muscle and cardiac outflow tract (OFT) myocardium, revealed unexpected complexity in development of these muscle groups. The Pitx2 homeobox gene functions in both cranial paraxial mesoderm, to regulate eye muscle, and in splanchnic mesoderm to regulate OFT development. Here, we investigated Pitx2 in branchiomeric muscle. Pitx2 was expressed in branchial arch core mesoderm and both Pitx2 null and Pitx2 hypomorphic embryos had defective branchiomeric muscle. Lineage tracing with a Pitx2cre allele indicated that Pitx2 mutant descendents moved into the first branchial arch. However, markers of both undifferentiated core mesoderm and specified branchiomeric muscle were absent. Moreover, lineage tracing with a Myf5cre allele indicated that branchiomeric muscle specification and differentiation were defective in Pitx2 mutants. Conditional inactivation in mice and manipulation of Pitx2 expression in chick mandible cultures revealed an autonomous function in expansion and survival of branchial arch mesoderm.

Animals↗
PubMed1990

A mesoderm-inducing factor produced by WEHI-3 murine myelomonocytic leukemia cells is activin A.

The first inductive interaction in amphibian development is mesoderm induction, during which a signal from the vegetal hemisphere of the blastula-staged embryo induces mesoderm from overlying equatorial cells. Recently, a number of 'mesoderm-inducing factors' (MIFs), which may be responsible for this interaction, have been discovered. Examples of these MIFs include members of the fibroblast growth factor family as well as members of the TGF-beta superfamily such as TGF-beta 2. In addition to these purified factors, several new sources of mesoderm-inducing activity have been described. One of the most potent of these is the murine myelomonocytic leukemia cell line WEHI-3. Even at high dilutions, conditioned medium from WEHI-3 cells induces isolated Xenopus animal pole regions to form a variety of mesodermal cell types. In this paper we show by several criteria, including N-terminal amino acid sequencing, Northern blotting and various functional assays, that the WEHI-MIF is activin A. Activins are known to modulate the release of follicle-stimulating hormone from cultured anterior pituitary cells and to cause the differentiation of two erythroleukemia cell lines. Our results, along with recent data from other laboratories, indicate that these molecules may also act in early development in the formation of the mesoderm.

Activins↗
PubMed1990

Isolation of the mouse Hox-2.9 gene; analysis of embryonic expression suggests that positional information along the anterior-posterior axis is specified by mesoderm.

It is rapidly becoming accepted that the vertebrate neural tube, in particular the hindbrain, develops into a segmented structure. After segment formation, cells in the neural tube do not cross segmental boundaries, and segment-specific gene expression is observed. However, it is not known what positional cues instruct the neural tube to express genes in this restricted manner. We have cloned a murine homeobox-containing gene, Hox-2.9, whose expression in the neural tube at E9.5 is restricted to a segment of the hindbrain known as rhombomere 4. A study of its expression pattern earlier in development revealed that prior to the start of neurulation (E7.5) Hox-2.9 is expressed within a posterior to the embryonic mesoderm that will participate in hindbrain formation. With the onset of neurulation, expression then becomes detectable in the neural plate as well, but only in the part that overlies the Hox-2.9-expressing mesoderm; it is not detected in the more anterior neuroectoderm that will form the future midbrain and forebrain. On the basis of these findings, we propose that the mesoderm is providing cues that serve to instruct the overlying neuroectoderm with respect to its position along the anteroposterior axis and that Hox-2.9 participates in or reflects this process. As neurulation continues and individual segments form, a second phase of expression is detected in the neural tube in which high levels of Hox-2.9 transcripts become restricted to rhombomere 4. Hox-2.9 expression is also detected in the developing branchial arch units of the hindbrain region, in a pattern that suggests to us that here, too, mesoderm is providing a localized signal that induces Hox-2.9 expression, in this case in endoderm of the pharynx and in superficial ectoderm. In general, we interpret the expression patterns of Hox-2.9 in the hindbrain region as suggesting that the specific mechanisms of pattern formation in mammals are fundamentally similar to those of amphibians and avians - i.e. anteroposterior positional information is acquired by mesoderm, mesoderm induces positional values within (neuro-) ectoderm and endoderm, and both events occur within a restricted window of time.

Amino Acid Sequence↗
PubMed1992

Induction of dorsal and ventral mesoderm by ectopically expressed Xenopus basic fibroblast growth factor.

Peptide growth factors from the fibroblast growth factor (FGF) and transforming growth factor-beta families are likely regulators of mesoderm formation in the early Xenopus embryo. Although basic FGF is found in the Xenopus embryo at the correct time and at sufficient concentrations to suggest that it is the FGF-type inducer, the lack of a secretory signal sequence in the basic FGF peptide has raised questions as to its role in the inductive process. We show here that Xenopus basic FGF can ectopically induce mesoderm when translated from injected synthetic RNA within the cells of a Xenopus embryo. Basic FGF produced in this manner is able to induce the formation of both dorsal and ventral mesoderm with the type of mesoderm formed dependent on the inherent dorsal-ventral polarity of the animal hemisphere. Surprisingly, although Xenopus basic FGF produced from the injected mRNA has a potent mesodermalizing effect on animal hemisphere cells, virtually no phenotypic effect is observed with intact embryos. These results suggest that the role of Xenopus basic FGF is to specify the size of the marginal zone, and synergistically with a dorsally localized prepatterning signal, to initially establish the dorsal-ventral axis of the mesoderm.

Animals↗
PubMed1993

A role for the mesoderm in endodermal migration and morphogenesis in Drosophila.

The endodermal midgut arises from two primordia, the anterior midgut (AMG) primordium and the posterior midgut (PMG) primordium, which are separated by almost the entire length of the Drosophila embryo. To form the midgut, these two parts have to extend towards each other and to fuse laterally on both sides of the yolk. Shortly before and during that movement, AMG and PMG are arranged as mesenchymal cell masses, but later the midgut cells form an epithelium. We show that these two aspects of midgut development, migration of AMG and PMG and transition to an epithelium, depend on the mesoderm. The extension of the midgut primordia is achieved by cell migration along the visceral mesoderm which forms a continuous layer of cells within the germ band. In mutant embryos lacking the entire mesoderm or failing to differentiate the visceral mesoderm, AMG and PMG are formed but do not migrate properly. In addition, they fail to form an epithelium and instead either remain as compact cell masses anterior and posterior to the yolk (in twist and snail mutant embryos) or only occasionally wrap around the yolk before embryogenesis is completed (in tinman-deficient embryos). We conclude that the visceral mesoderm serves as a substratum for the migrating endodermal cells and that the contact between visceral mesoderm and endoderm is required for the latter to become an epithelium.

Animals↗