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PubMed2000

Distinct promoter elements mediate endodermal and mesodermal expression of the HNF1alpha promoter in transgenic Xenopus.

The gene encoding the tissue specific transcription factor HNF1alpha is expressed in vertebrates in tissues of endodermal origin such as the liver and the gut as well as in the kidney, a mesoderm derived organ. Using a 6 kb HNF1alpha promoter fragment linked to GFP we observed green fluorescence in transgenic embryos restricted to the liver and gut as well as to the pronephros, the embryonic kidney. By deletion and mutation analysis of the HNF1alpha promoter we succeeded in dissecting the HNF1alpha promoter into two entities that are either active in the endoderm or the mesoderm. In conclusion, our data establish that the generation of transgenic Xenopus allows the functional dissection of promoters in the context of the entire organism.

Animals↗

PubMed1994

Mesodermal patterning by an inducer gradient depends on secondary cell-cell communication.

BACKGROUND: Gradients of inducing molecules, or morphogens, could impose pattern on early embryos. Although there are candidates for morphogens in several systems, it is not well understood how cells might translate differences in extracellular inducer concentration into an orderly arrangement of cell types. With this question in mind, we have re-examined mesodermal patterning in Xenopus in response to the secreted growth factor activin. Previous work has shown that activin can initiate the formation of a variety of mesodermal tissues in a concentration-dependent fashion. We have sought to disentangle the roles played by individual cell responses to activin and subsequent interactions among induced cells in producing this outcome. RESULTS: We find that the initial response of dispersed cells to activin concentration is unexpectedly simple, showing neither the thresholds of activin concentration nor the distinct domains of gene expression that characterize the later response. The eventual emergence of an ordered series of coherent differentiation steps requires the reaggregation of the induced cells, implying that secondary interactions occur. Furthermore, when cells induced at different doses of activin are mixed, the final response apparently represents a consensus, rather than a mosaic, of the mixed populations. CONCLUSIONS: We conclude that communication among responding cells underlies much of the remarkable patterning influence of activin. Moreover, we suggest that these findings can inform thinking about how inducer gradients might act in other systems, shifting emphasis from the initial response of cells to inducer concentration toward the elaboration of complex pattern by secondary interactions.

Actins↗

PubMed2001

The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm.

Development of the arterial pole of the heart is a critical step in cardiogenesis, yet its embryological origin remains obscure. We have analyzed a transgenic mouse line in which beta-galactosidase activity is observed in the embryonic right ventricle and outflow tract of the heart and in contiguous splanchnic and pharyngeal mesoderm. The nlacZ transgene has integrated upstream of the fibroblast growth factor 10 (Fgf10) gene and comparison with the expression pattern of Fgf10 in pharyngeal mesoderm indicates transgene control by Fgf10 regulatory sequences. Dil labeling shows a progressive movement of cells from the pharyngeal arch region into the growing heart tube between embryonic days 8.25 and 10.5. These data suggest that arterial pole myocardium originates outside the classical heart field.

Animals↗

PubMed2003

From mesoderm to blood islands: patterns of key molecules during yolk sac erythropoiesis.

Several identified genes play key roles in the specification of the blood-forming system, from commitment of mesoderm to differentiation of hemopoietic and endothelial cells. We have thoroughly analyzed the expression dynamics of some of these genes during yolk sac erythropoiesis in the chick embryo. The study includes transcription factors which are known to participate in multimeric complexes: GATA-1, -2, SCL/tal-1 and Lmo2 (whose avian orthologue we have cloned), VEGF-R2, a critical regulator of hemopoietic and endothelial commitment, and hemoglobin used as a marker of the last step in erythroid differentiation. Several findings were unexpected. (1) Two distinct patterns were revealed for GATA-2, first: low expression, ubiquitous in all mesodermal cells, as soon as cells ingress through the primitive streak; secondly: high, blood island-specific expression. (2) VEGF-R2 is coexpressed with GATA-2 at the level of the primitive streak. (3) SCL and Lmo2 expression is restricted to presumptive hemangioblasts. (4) The up-regulation of GATA-2 in newly formed blood islands is shortly followed by GATA-1 expression. (5) Lmo2 is up-regulated in blood island angioblasts thus appearing as one of the earliest markers for endothelial cell commitment. VEGF-R2 is down-regulated in hemopoietic cells prior to GATA-2, SCL/tal-1, Lmo2 and GATA-1 in erythroblasts.

Amino Acid Sequence↗

PubMed2000

Endometrial mesodermal mixed tumor occurring after tamoxifen treatment: report on a new case and review of the literature.

BACKGROUND: Anti oestrogenic treatment is widely used for breast cancer treatment and prevention of recurrence. Because of concomitant estrogenic effects, tamoxifen exerts carcinogenic properties on the endometrium. Although secondary endometrial cancers usually present as pure adenocarcinomas, other types of rare tumors have also been reported. PATIENTS AND METHODS: Herein we describe the clinical, pathological as well as therapeutic aspects of a new case of endometrial mesodermal mixed tumor occurring after long-term tamoxifen therapy. RESULTS: The present case occured five years after cessation of a five years tamoxifen treatment. The patient failed to respond to doxorubicin and cyclophosphamide when combined to 5-fluorouracil (5-FU), but she reached complete response when the same two drugs were used with carboplatin, suggesting the potential usefullness of platinum derivatives. CONCLUSIONS: A longer latency period might be observed for endometrial mesodermal mixed tumors as compared to adenocarcinomas and could justify a prolonged clinical and ultrasonographic follow-up of patients during and after tamoxifen treatment. When indicated, chemotherapy might require the use of platinum derivatives in this particular type of secondary tumor.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Detection and characterization of an activity which aligns mesodermal cells into parallel arrays.

A cell line of mesodermal origin, FS9, was found to release a Cell Orienting Factor into its culture medium. In contrast with the random migration of controls, the orienting activity causes migrating mesenchymal cells to form an orderly "halo' surrounding tissue explants; individual cells and their cytoskeletons are elongated and parallel to each other but at right angle to the explant. No effect on the rate of cell movement was apparent. The orienting activity could be quantified by counting the number of cells found within strings radiating at right angles to a single tissue explant in the presence of FS9 conditioned medium or by using NIH image analysis. A dose dependent relationship with half maximal activity occurring at a 25% dilution of conditioned medium was observed. Cells that migrated randomly in the absence of conditioned medium became oriented within 4 h of exposure to 50% conditioned medium. Conversely, when the conditioned medium was removed, parallel alignment was rapidly lost. The orienting activity was found in conditioned media from a variety of mesodermal derivatives. Transformation of Balb/c 3T3 cells using EJ-ras oncogene led to augmented production of the activity. Furthermore, insulin was required in serum-free medium to support its production, Laminin, fibronectin and collagen and a range of pure cytokines, neither promoted nor inhibited orientation. Cell alignment was also unaffected by treatments which interfered with cell-substrate interactions and motility including the addition of the RGD peptide or anti-integrin beta 1 and beta 3 antibodies. A protein is likely to be involved since the activity was heat and trypsin sensitive and non-dialysable. The possibility is discussed that the orienting activity is a novel protein(s) which alters intercellular interactions to promote the formation of an aligned pattern by migrating mesenchymal cells.

3T3 Cells↗

PubMed1980

Determination and cellular commitment in the embryonic amphibian mesoderm.

In classical embryology, the term 'determination' was used to describe the process by which a region of the embryo became committed to form a particular part of the body and it was understood that there was a particular stage of development at which determination occurred with respect to each decision. Some authors insisted that only an irreversible commitment should be described as determination, but this leaves undefined the nature of the preceding events involved in its establishment. We show here that there may be several stages of commitment for an organ rudiment that can be distinguished from one another by the use of different methods for altering the pathway of development. We have investigated the region of the amphibian mesoderm that is destined to become somitic muscle in the course of normal development and applied to it a variety of isolation and grafting techniques. The results, which show an extensive period of lability within this region, can be used to explain how pattern formation might occur within the dorsoventral axis of the mesoderm.

Ambystoma↗

PubMed1998

Smad2 role in mesoderm formation, left-right patterning and craniofacial development.

Signalling by the transforming growth factor-beta (TGF-beta) superfamily of proteins depends on the phosphorylation and activation of SMAD proteins by heteromeric complexes of ligand-specific type I and type II receptors with serine/threonine-kinase activity. The vertebrate SMAD family includes at least nine members, of which Smad2 has been shown to mediate signalling by activin and TGF-beta. In Xenopus, Smad2 can induce dorsal mesoderm, mimicking Vg-1, activin and nodal. Here we investigate the function of Smad2 in mammalian development by generating two independent Smad2 mutant alleles in mice by gene targeting. We show that homozygous mutant embryos fail to form an organized egg cylinder and lack mesoderm, like mutant mice lacking nodal or ActRIB, the gene encoding the activin type-I receptor. About 20 per cent of Smad2 heterozygous embryos have severe gastrulation defects and lack mandibles or eyes, indicating that the gene dosage of Smad2 is critical for signalling. Mice trans-heterozygous for both Smad2 and nodal mutations display a range of phenotypes, including gastrulation defects, complex craniofacial abnormalities such as cyclopia, and defects in left-right patterning, indicating that Smad2 may mediate nodal signalling in these developmental processes. Our results show that Smad2 function is essential for early development and for several patterning processes in mice.

Abnormalities, Multiple↗

PubMedDate not supplied

Proto-oncogene c-fos expression in growth regions of fetal bone and mesodermal web tissue.

The phylogenic conservation of the proto-oncogene c-fos suggests that this gene product is required for normal metabolic processes. Investigations into the transcription pattern of c-fos in normal tissues and cells have revealed expression during development, differentiation and growth which is dependent to a large extent on external signals transferred by growth factors. The complex pattern of stage and tissue-specific expression has raised the hypothesis that the c-fos gene product might function in the control of either proliferation or differentiation. However, no detailed analysis is yet available concerning the normal expression of c-fos during embryonic and fetal development. Interestingly, recent data derived from studies in transgenic mice reveal that the biological effect of overexpression of exogenous fos is restricted to the developing bone tissue and T-cell development of the mice, perhaps signifying that these cells represent a physiological target tissue of the proto-oncogene fos. Thus, to gain deeper insight into the functional role of the c-fos gene product during physiological processes, it is a requirement to carry out a detailed analysis of the localization and cell-type specificity of c-fos expression in normal mouse embryos. Using the technique of in situ hybridization, we demonstrate here that stage-specific expression of the proto-oncogene c-fos in mouse embryos is restricted to the perichondrial growth regions of the cartilaginous skeleton. Moreover, we found strong c-fos transcription in web-forming mesodermal cells, which are also characterized by a stage-specific high growth capacity. Our results suggest a tissue-specific regulatory role of c-fos during differentiation-dependent growth processes of fetal bone and mesodermal web tissue.

Animals↗

PubMed1988

Domain of Ultrabithorax expression in Drosophila visceral mesoderm from autoregulation and exclusion.

Domains of differential homeotic gene activity are formed at specific positions along the anteroposterior axis of the early Drosophila embryo. Homeotic genes are required continuously throughout development, so that homeotic gene activity has to be maintained independently of the positional information provided in the early embryo. In the ectoderm, the domains of homeotic gene activity partially overlap, but we have found that in the visceral mesoderm at least three of these genes are expressed in adjacent and mutually exclusive domains. It has been proposed that stable, sharply demarcated domains of this type could be established if a homeotic gene product stimulated its own expression locally and inhibited the expression of other homeotic genes, which Meinhardt has termed autocatalysis and mutual exclusion respectively. Furthermore, autocatalysis of this kind can in principle account for the maintenance of homeotic gene activity throughout development. We find that the unique domain of Ultrabithorax (Ubx) expression in the visceral mesoderm is dependent both on autocatalysis and on an exclusion mechanism: Ubx product is required for its own synthesis, whereas the product of the posteriorly adjacent gene abdominal-A represses Ubx expression.

Animals↗

PubMed1990

Cloning of the T gene required in mesoderm formation in the mouse.

The murine developmental mutation T identifies an essential gene in mesoderm formation. Embryos lacking normal gene activity fail to form the notochord, the entire posterior region and the allantois, and die at about 10 days of gestation. We have isolated the T gene using a combination of molecular and genetic techniques, thus making molecular tools available to study processes underlying mesoderm formation in the mouse.

Alleles↗

PubMed1990

Activin-like factor from a Xenopus laevis cell line responsible for mesoderm induction.

Induction of mesoderm during early amphibian embryogenesis can be mimicked in vitro by adding growth factors, including heparin-binding and type-beta transforming growth factors (TGF-beta), to isolated ectoderm explants from Xenopus laevis embryos. Although the mesoderm-inducing factor (MIF) from X. laevis XTC cells (XTC-MIF) has properties similar to TGF-beta, this factor is still unidentified. Recently, we obtained a number of homogeneous cell lines from the heterogeneous XTC population, which differ in their MIF production. Only one, XTC-GTX-11, produced MIF, although it was similar to the rest of the clones in its production of known growth factors, including TGF-beta activity. This observation, together with the identification of activin A as a potent MIF led us to study the parallel activities of MIF and activin. Here we report an analysis of activin-like activity from XTC cells and some of the XTC clones, including XTC-GTX-11. There is a clear consistent correlation between MIF activity and presence of activin activity, indicating that XTC-MIF is the Xenopus homologue of mammalian activin.

Activins↗

PubMed1992

A truncated activin receptor inhibits mesoderm induction and formation of axial structures in Xenopus embryos.

Activins can induce mesoderm in embryonic explants and have been proposed as the natural inducer in Xenopus. A mutant activin receptor that inhibits activin signalling is used to show that activin is required for the induction of mesoderm in vivo and the patterning of the embryonic body plan. Blocking the activin signal transduction pathway also reveals autonomous induction of a neural marker and unmasks a relationship between activin and fibroblast growth factor.

Activin Receptors↗

PubMed2006

Mesodermal Wnt2b signalling positively regulates liver specification.

Endodermal organs such as the lung, liver and pancreas emerge at precise locations along the primitive gut tube. Although several signalling pathways have been implicated in liver formation, so far no single gene has been identified that exclusively regulates liver specification. In zebrafish, the onset of liver specification is marked by the localized endodermal expression of hhex and prox1 at 22 hours post fertilization. Here we used a screen for mutations affecting endodermal organ morphogenesis to identify a unique phenotype: prometheus (prt) mutants exhibit profound, though transient, defects in liver specification. Positional cloning reveals that prt encodes a previously unidentified Wnt2b homologue. prt/wnt2bb is expressed in restricted bilateral domains in the lateral plate mesoderm directly adjacent to the liver-forming endoderm. Mosaic analyses show the requirement for Prt/Wnt2bb in the lateral plate mesoderm, in agreement with the inductive properties of Wnt signalling. Taken together, these data reveal an unexpected positive role for Wnt signalling in liver specification, and indicate a possible common theme for the localized formation of endodermal organs along the gut tube.

Animals↗

PubMed1998

Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1.

The basic helix-loop-helix (bHLH) transcription factors, Hand1 and Hand2 (refs 1,2), also called eHand/Hxt/Thing1 and dHand/Hed/Thing2 (refs 3,4), respectively, are expressed in the heart and certain neural-crest derivatives during embryogenesis. In addition, Hand1 is expressed in extraembryonic membranes, whereas Hand2 is expressed in the deciduum. Previous studies have demonstrated that Hand2 is required for formation of the right ventricle of the heart and the aortic arch arteries. We have generated a germline mutation in the mouse Hand1 gene by replacing the first coding exon with a beta-galactosidase reporter gene. Embryos homozygous for the Hand1 null allele died between embryonic days 8.5 and 9.5 and exhibited yolk sac abnormalities due to a deficiency in extraembryonic mesoderm. Heart development was also perturbed and did not progress beyond the cardiac-looping stage. Our results demonstrate important roles for Hand1 in extraembryonic mesodermal and heart development.

Animals↗

PubMed1997

Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND.

dHAND and eHAND are related basic helix-loop-helix (bHLH) transcription factors that are expressed in mesodermal and neural crest-derived structures of the developing heart. In contrast to their homogeneous expression during avian cardiogenesis, during mouse heart development we show that dHAND and eHAND are expressed in a complementary fashion and are restricted to segments of the heart tube fated to form the right and left ventricles, respectively. dHAND and eHAND represent the earliest cardiac chamber-specific transcription factors yet identified. Targeted gene deletion of dHAND in mouse embryos resulted in embryonic lethality at embryonic day 10.5 from heart failure. Our description of the cardiac phenotype of dHAND mutant embryos is the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches and reveals a novel cardiogenic subprogramme for right ventricular development.

Animals↗

PubMed1993

The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma.

The tumour suppressor gene WT1 encodes a transcription factor expressed in tissues of the genito-urinary system. Inactivation of this gene is associated with the development of Wilms tumour a pediatric kidney cancer. We show that WT1 is also expressed at high levels in many supportive structures of mesodermal origin in the mouse. We also describe a case of adult human mesothelioma, a tumour derived from the peritoneal lining, that contains a homozygous point mutation within WT1. This mutation, within the putative transactivation domain, converts the protein from a transcriptional repressor of its target sequence to a transcriptional activator. The role of WT1 in normal development thus extends to diverse structures derived from embryonic mesoderm and disruption of WT1 function contributes to the onset of adult, as well as pediatric, tumours.

Adult↗

PubMed2006

Mesoderm induction: from caps to chips.

Vertebrate mesoderm induction is one of the classical problems in developmental biology. Various developmental biology approaches, particularly in Xenopus and zebrafish, have identified many of the key factors that are involved in this process and have provided major insights into how these factors interact as part of a signalling and transcription-factor network. These data are beginning to be refined by high-throughput approaches such as microarray assays. Future challenges include understanding how the prospective mesodermal cells integrate the various signals they receive and how they resolve this information to regulate their morphogenetic behaviours and cell-fate decisions.

Animals↗