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PubMed2002

The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression.

The POU homeodomain protein Oct-4 and the Forkhead Box protein FoxD3 (previously Genesis) are transcriptional regulators expressed in embryonic stem cells. Down-regulation of Oct-4 during gastrulation is essential for proper endoderm development. After gastrulation, FoxD3 is generally down-regulated during early endoderm formation, although it specifically remains expressed in the embryonic neural crest. In these studies, we have found that Oct-4 and FoxD3 can bind to identical regulatory DNA sequences. In addition, Oct-4 physically interacted with the FoxD3 DNA-binding domain. Cotransfection of Oct-4 and FoxD3 expression vectors activated the osteopontin enhancer, which is expressed in totipotent embryonic stem cells. FoxA1 and FoxA2 (previously HNF-3alpha and HNF-3beta) are Forkhead Box transcription factors that participate in liver and lung formation from foregut endoderm. Although FoxD3 activated the FoxA1 and FoxA2 promoters, Oct-4 inhibited FoxD3 activation of the FoxA1 and FoxA2 endodermal promoters. These data indicate that Oct-4 functions as a corepressor of FoxD3 to provide embryonic lineage-specific transcriptional regulatory activity to maintain appropriate developmental timing.

Binding Sites↗
PubMed1996

Differentiation of F9 teratocarcinoma stem cells to primitive endoderm is regulated by the Gialpha2/Gsalpha axis via phospholipase C and not adenylylcyclase.

Morphogen-induced decline in Gialpha triggers F9 teratocarcinoma stem cells to progress to primitive endoderm via activation of protein kinase C and mitogen-activated protein kinase (Gao, P., and Malbon, C. C. (1996) J. Biol. Chem. 271, 9002-9008). Constitutive expression of Gialpha2 blocks, whereas expression of Gsalpha provokes, progression to primitive endoderm, permitting identification of the effectors of the response-utilizing chimera created between Gialpha2 and Gsalpha. N-terminal substitution of Gsalpha with Gialpha2 sequence to create chimera Gialpha2 (1-54)/Gsalpha produced a chimera that activated adenylylcyclase but abolished progression to primitive endoderm and activation of phospholipase C. C-terminal substitution of Gsalpha with Gialpha2 sequence to Gsalpha/Gialpha2 (320-355) enhanced the ability of Gsalpha to promote progression. The Q205L-activated mutant of Gialpha2 suppresses, whereas the G225T-activated mutant of Gsalpha strongly activates phospholipase C and progression in these cells. The N-terminal region of Gsalpha (residues 62-86) appears to act as a dominant switch for the Gsalpha- (activation) versus Gialpha2- (suppression) mediated control of phospholipase C and progression to primitive endoderm.

Adenylyl Cyclases↗
PubMed2003

Functions of HNF1 family members in differentiation of the visceral endoderm cell lineage.

The two members of the hepatocyte nuclear factor 1 (HNF1) transcription factor family, HNF1 and variant HNF1 (vHNF1), show a strong homology in their atypical POU-homeodomain and dimerization domain but differ in their transactivation domains. Moreover, two vHNF1 isoforms generated by alternative splicing are present in all tissues expressing this gene. vHnf1-deficient mouse embryos die soon after implantation due to defective visceral endoderm formation, an extraembryonic tissue essential for development and survival of the embryo proper. In contrast, invalidation of Hnf1, which is expressed at later developmental stages than vHnf1, does not lead to embryonic lethality or developmental defects. To examine the specific or potential equivalent functions of vHNF1 isoforms and HNF1 during the process of visceral endoderm differentiation, we stably reexpressed these factors in vHnf1-deficient embryonic stem cells. Analysis of these embryonic stem cells upon differentiation into embryoid bodies shows that vHNF1 isoforms exhibit specific behaviors depending on particular target genes and cooperate in the establishment of a functional visceral endoderm. Furthermore, forced expression of HNF1 in vHnf1-deficient embryonic stem cells fully restores the formation of a mature visceral endoderm with the correct expression profile of early and late markers of this lineage. Thus, in this context, HNF1 functionally replaces both vHNF1 isoforms, suggesting that the different developmental functions of these transcription factors are mainly due to the acquisition of novel expression patterns.

Alternative Splicing↗
PubMedDate not supplied

CD9-alpha6beta1 interactions in migratory parietal endoderm cells.

Tetraspanins modulate the function of a variety of membrane proteins, including integrin receptors. We show here that the tetraspanin CD9 preferentially coimmunoprecipitates with the alpha6beta1 integrin heterodimer in F9-derived parietal endoderm cells in comparison to F9 stem cells. We also show that CD9 function-blocking antibody inhibits parietal endoderm migration in an embryoid body outgrowth assay. In addition, both CD9 and alpha6beta1 colocalize with vinculin to apparent focal adhesion sites in parietal endoderm cells. The data presented here suggests a role for CD9 in localizing the integrin to the focal adhesion. In addition, the data suggest a role for CD9 in alpha6beta1 mediated migration of parietal endoderm.

Animals↗
PubMed1990

Gene expression in visceral endoderm: a comparison of mutant and wild-type F9 embryonal carcinoma cell differentiation.

We have examined the abundance and cell specificity of several mRNAs that are regulated during the retinoic acid (RA)-induced differentiation of F9 embryonal carcinoma cells to visceral endoderm. The experiments confirmed the multistep nature of this process by demonstrating the expression of the ERA-1/Hox 1.6 message within 6 h after RA addition; the expression of messages specific for the extracellular matrix proteins laminin B1 and B2, and collagen IV(alpha 1) between days 4 and 12; and the expression of two visceral endoderm markers, alpha-fetoprotein (AFP) and H19, by days 8-15. In situ hybridization experiments revealed that the collagen IV(alpha 1) mRNA is restricted to the outer cell layer of F9 cell aggregates regardless of the presence or absence of RA. Laminin B1 and B2 mRNAs are concentrated in the outer cell layer of RA-treated aggregates although significant levels of message are also observed within the interior cells of the aggregates. Unexpectedly, AFP mRNA is detectable in only a subset of the outer cells of F9 cell aggregates grown 15 d in the presence of RA. The results obtained from wild-type F9 cells were compared with those from a mutant F9 cell line, RA-5-1, which was previously shown to synthesize collagen IV containing six- to ninefold less 4-hydroxyproline than that in wild-type F9 cells. RA-5-1 cells exhibit four- to sixfold less of the mRNAs encoding two visceral endoderm proteins, AFP and H19, than wild-type F9 cells after RA treatment of RA-5-1 aggregates. RA-5-1 cells, however, do exhibit an RA-associated increase in the level of ERA-1/Hox 1.6 mRNA within 6 h after adding RA. Although the collagen IV protein level is similar in wild-type F9 and RA-5-1 aggregates, the collagen IV(alpha 1) message level is 6-20-fold greater in aggregates of mutant cells than in aggregates of wild-type cells. Moreover, in situ hybridizations showed that this message is evenly distributed throughout the RA-5-1 aggregates rather than restricted to the outer cell layers as it is in wild-type F9 aggregates. These results suggest that abnormal collagen IV expression and localization are associated with decreased expression of the visceral endoderm markers, AFP and H19, in RA-5-1 cell aggregates.

Animals↗
PubMed1997

A CREB-binding site as a target for decapentaplegic signalling during Drosophila endoderm induction.

Decapentaplegic (Dpp) is an extracellular signal of the transforming growth factor-beta family with multiple functions during Drosophila development. For example, it plays a key role in the embryo during endoderm induction. During this process, Dpp stimulates transcription of the homeotic genes Ultrabithorax in the visceral mesoderm and labial in the subjacent endoderm. Here, we show that a cAMP response element (CRE) from an Ultrabithorax enhancer mediates Dpp-responsive transcription in the embryonic midgut, and that endoderm expression from a labial enhancer depends on multiple CREs. Furthermore, the Drosophila CRE-binding protein dCREB-B binds to the Ultrabithorax CRE, and ubiquitous expression of a dominant-negative form of dCREB-B suppresses CRE-mediated reporter gene expression and reduces labial expression in the endoderm. Therefore, a CREB protein may act as a nuclear target, or as a partner of a nuclear target, for Dpp signalling in the embryonic midgut.

Activating Transcription Factor 1↗
PubMed2001

The transcription factors MTF-1 and USF1 cooperate to regulate mouse metallothionein-I expression in response to the essential metal zinc in visceral endoderm cells during early development.

During early development of the mouse embryo, expression of the metallothionein-I (MT-I) gene is heightened specifically in the endoderm cells of the visceral yolk sac. The mechanisms of regulation of this cell-specific pattern of expression of metallothionein-I are unknown. However, it has recently been shown that MTF-1, functioning as a metalloregulatory transcription factor, activates metallothionein genes in response to the essential metal zinc. In contrast with the metallothionein genes, MTF-1 is essential for development; null mutant embryos die due to liver degeneration. We report here that MTF-1 is absolutely essential for upregulation of MT-I gene expression in visceral endoderm cells and that optimal expression also involves interactions of the basic helix-loop-helix upstream stimulatory factor-1 (USF1) with an E-box1-containing sequence at -223 bp in the MT-I promoter. Expression of MT-I in visceral endoderm cells was dependent on maternal dietary zinc. Thus, the essential metal, zinc, apparently provides the signaling ligand that activates cell-specific MT-I expression in visceral endoderm cells.

Alkaline Phosphatase↗
PubMed2004

Placental yolk sac tumor with divergent endodermal differentiation.

We report an intraplacental germ cell tumor that was an incidental finding in the placenta of a 34-year-old woman. On pathologic examination, the 4.0-cm tumor was well circumscribed with a thin fibrous capsule. It exhibited three major histologic patterns within a mesenchyme-like myxoid background: a primitive endodermal component, a well-differentiated enteric glandular endodermal component, and a component of fetal hepatic tissue. The primitive endodermal component, the hepatic component, and many parts of the enteric endodermal glandular component were immunoreactive for alpha-fetoprotein. We considered the lesion to be a unique example of a placental yolk sac tumor and only the second reported case of a placental yolk sac tumor.

Adult↗
PubMed1996

Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control.

We have studied the initial development of pluripotent gut endoderm to hepatocytes using a tissue explant system from mouse embryos. We not only find cellular interactions that specify hepatic differentiation but also those that block hepatogenesis in regions of the endoderm that normally give rise to other tissues. The results implicate both positive and negative signaling in early hepatic specification. In vivo footprinting of the albumin enhancer in precursor gut endoderm shows that the transcriptionally silent but potentially active chromatin is characterized by occupancy of an HNF-3 site. Upon hepatic specification, a host of other factors bind nearby sites as the gene becomes active. Genes in pluripotent cells therefore may be marked for potential expression by entry points in chromatin, where additional factors bind during cell type specification. The findings also provide insight into the evolutionary origin of different endodermal cell types.

Actins↗
PubMed1999

Gata5 is required for the development of the heart and endoderm in zebrafish.

The mechanisms regulating vertebrate heart and endoderm development have recently become the focus of intense study. Here we present evidence from both loss- and gain-of-function experiments that the zinc finger transcription factor Gata5 is an essential regulator of multiple aspects of heart and endoderm development. We demonstrate that zebrafish Gata5 is encoded by the faust locus. Analysis of faust mutants indicates that early in embryogenesis Gata5 is required for the production of normal numbers of developing myocardial precursors and the expression of normal levels of several myocardial genes including nkx2.5. Later, Gata5 is necessary for the elaboration of ventricular tissue. We further demonstrate that Gata5 is required for the migration of the cardiac primordia to the embryonic midline and for endodermal morphogenesis. Significantly, overexpression of gata5 induces the ectopic expression of several myocardial genes including nkx2.5 and can produce ectopic foci of beating myocardial tissue. Together, these results implicate zebrafish Gata5 in controlling the growth, morphogenesis, and differentiation of the heart and endoderm and indicate that Gata5 regulates the expression of the early myocardial gene nkx2.5.

Amino Acid Sequence↗
PubMed2006

Combined ectopic expression of Pdx1 and Ptf1a/p48 results in the stable conversion of posterior endoderm into endocrine and exocrine pancreatic tissue.

Patterning of the embryonic endoderm into distinct sets of precursor cells involves the precisely regulated activities of key transcription regulators. Ectopic, pan-endodermal activation of XPtf1a/p48 during pancreas precursor cell stages of Xenopus embryogenesis results in an expansion of the pancreatic territory, precisely within the borders of XlHbox8 expression. A combination of both activities is sufficient to expand the pancreatic precursor cell population also into more posterior portions of the endoderm. Both treatments result in the formation of a giant pancreas that persists up to late tadpole stages of development and carries both supernumerary endocrine and exocrine cells. A combination of XPtf1a/p48 and XlHbox8 is thus sufficient to convert nonpancreatic endodermal cells into pancreatic precursor cells.

Animals↗
PubMed2001

Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes.

The mechanisms by which the epithelium of the digestive tract and its associated glands are specified are largely unknown. One clue is that several transcription factors are expressed in specific regions of the endoderm prior to and during organogenesis. Pdx-1, for example, is expressed in the duodenum and pancreas and Pdx-1 inactivation results in an arrest of pancreatic development after buds formation. Similarly, ngn3 is transiently expressed in the developing pancreas and a knockout results in the absence of endocrine cells. This paper focuses on the question of whether these and other transcription factors, known to be necessary for pancreatic development, are also sufficient to drive a program of pancreatic organogenesis. Using in ovo electroporation of chick embryos, we show that ectopic expression of Pdx-1 or ngn3 causes cells to bud out of the epithelium like pancreatic progenitors. The Pdx-1-expressing cells extinguish markers for other nonpancreatic regions of the endoderm and initiate, but do not complete, pancreatic cytodifferentiation. Ectopic expression of ngn3 is sufficient to turn endodermal cells of any region into endocrine cells that form islets expressing glucagon and somatostatin in the mesenchyme. The results suggest that simple gene combinations could be used in stem cells to achieve specific endodermal tissue differentiation.

Animals↗
PubMed2005

High-throughput functional screen of mouse gastrula cDNA libraries reveals new components of endoderm and mesoderm specification.

This study describes a cross-species functional screen of mouse gastrula cDNA libraries for components of endoderm and mesoderm specification. Pools of 96 cDNAs from arrayed mouse gastrula cDNA libraries were transcribed into mRNA and injected into either the presumptive mesoderm or the ectoderm of one-cell Xenopus laevis embryos. Injected embryos were examined at gastrula stage by in situ hybridization with endoderm or mesoderm markers. Using this approach, we screened over 700 pools or approximately 60,000 cDNAs. We identified 17 unique cDNAs that function during mesoderm and/or endoderm specification and 16 that cause general morphology changes. Identified molecules fall into eight general functional groups as follows: cell cycle components (seven), transcription factors (four), extracellular secreted molecules (seven), transmembrane receptors (one), intracellular signaling components (five), microtubule components (two), metabolism molecules (three), and unknown (four). Several of the genes we identified would not have been predicted to be involved in endoderm or mesoderm specification, highlighting the usefulness of nonbiased screening approaches. This includes Otx2, which we show is a downstream target of Xsox17beta. The speed, low cost, and high efficiency of this cross-species screen makes it an ideal method for examining cDNAs from difficult-to-obtain sources. Therefore, this approach complements the current mouse molecular genetics systems and provides a powerful means for the genome-wide examination of mammalian gene function.

Animals↗
PubMed2005

TGF-beta signaling potentiates differentiation of embryonic stem cells to Pdx-1 expressing endodermal cells.

Embryonic stem (ES) cells have the capacity to differentiate to every cell type that constitutes fetal or adult tissues. To trace and quantitatively assess the differentiation of ES cells into gut endodermal cells, we used an ES cell line with the lacZ gene inserted into the pdx-1 locus. Targeted mutations of pdx-1 in mice demonstrate that pdx-1 is required for pancreatic and rostral duodenal development; therefore, pdx-1 serves as an excellent early gut regional specific marker. When these ES cells were differentiated by removal of leukemia inhibitory factor (LIF), only fractional cells turned into lacZ positive, which indicates pancreatic-duodenal differentiation. Co-cultivation of ES cells with pancreatic rudiments induced a significant increase in the proportion of lacZ positive cell numbers and this increase was further enhanced by forced expression of a chick putative endoderm inducer gene, cmix. Transforming growth factor (TGF)-beta2 mimicked the effects of pancreatic rudiments and this effect was enhanced by cmix expression. Expression analysis showed over-expression of cmix induced endodermal marker genes. These data indicate that one can make use of this knowledge on molecular events of embryonic development to drive ES cells to differentiate into pdx-1 expressing endodermal cells in vitro.

Animals↗
PubMed1981

The extraembryonic endodermal differentiation and polyploidization of embryonal carcinoma cells in vitro.

Embryonal carcinoma cells (EC cells) can form a wide variety of differentiated cell types and thus resemble the pluripotential stem cells of the normal embryo. Certain EC cell derivatives acquire the biochemical and morphological features of primitive endoderm and have been called 'END' or endodermlike cells. Although these have also been called 'giant' because of their large size, their nuclear DNA contents are not known. Since cell size often corresponds to DNA content and primitive endoderm becomes polyploid during the course of normal development, EC-derived endoderm has been studied cytophotometrically. Thus, EC- and embryo-derived endoderm were found to be similar in that both of these tissues undergo polyploidization. Moreover, the polyploid cells of either EC or embryonic origin do not appear to be terminal cell types, since they can occasionally enter renewed cell division in spite of their large size.

Animals↗
PubMed1984

A scanning electron microscope study of the extraembryonic endoderm of the 8th-day mouse embryo.

Late primitive streak embryos were dissected to reveal the junction between the visceral (VE) and parietal (PE) extraembryonic endoderm. Scanning electron microscopy showed that the two cell types differ markedly in their surface morphology and intercellular organization: the VE cells have numerous apical microvilli and form part of a continuous epithelial layer, while the smoother PE cells are scattered individually over the surface of Reichert's membrane. One interpretation of the morphology of the junction between the two tissues is that visceral endoderm cells in this region are detaching from the epithelial layer, migrating on to Reichert's membrane and differentiating into parietal endoderm. Preparatory to this, the visceral endoderm cells in the junctional zone may undergo extensive reorganization of their surface membranes.

Animals↗
PubMed2004

Early endodermal expression of the Xenopus Endodermin gene is driven by regulatory sequences containing essential Sox protein-binding elements.

The Endodermin gene is expressed in the early endoderm and the Spemann organizer of Xenopus embryos. It has previously been shown to be a direct target of the early endodermal transcription factor Xsox17 (Clements et al., 2003, Mech Dev 120:337-348). Here we identify two adjacent control elements in the Endodermin promoter; these drive transcription of the gene in late-gastrula endoderm and contain consensus Sox-binding sites. We have analyzed one element in detail and show that it responds directly to Xsox17 and that the Sox sites are essential for endodermal expression in transgenic embryos. However, flanking regions on both sides are also essential, indicating that Xsox17 acts in concert with several DNA-binding partners.

Animals↗
PubMed1996

Biochemical evidence for membrane-bound endoderm-specific alkaline phosphatase in larvae of the ascidian, Halocynthia roretzi.

An endoderm-specific alkaline phosphatase with a molecular mass of 86 kDa has been found in tadpole larvae of the ascidian, Halocynthia roretzi. The histochemical staining of sections of the larvae revealed that the enzyme is a membrane-associated protein. Two distinct bands were detected by zymographic technique on SDS/PAGE of the membrane preparation of the larvae. The two enzymes can be solubilized from the membrane preparation by sodium cholate and separated from each other by Cibacron blue-3GA affinity chromatography. The 86-kDa enzyme is likely to be the endoderm-specific one because the susceptibilities to alkaline phosphatase inhibitors coincide between the 86-kDa enzyme and that found in the endoderm of larvae by histochemical staining. The endoderm-specific alkaline phosphatase was purified and its N-terminal amino acid sequence was found to show little similarity to those of other proteins.

Alkaline Phosphatase↗