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T Edlund

Publications and source records attributed to T Edlund.

At least 19 recordsLinked to original sources
PubMed1997

Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells.

The mammalian pancreas is a specialized derivative of the primitive gut endoderm and controls many homeostatic functions through the activity of its component exocrine acinar and endocrine islet cells. The LIM homeodomain protein ISL1 is expressed in all classes of islet cells in the adult and its expression in the embryo is initiated soon after the islet cells have left the cell cycle. ISL1 is also expressed in mesenchymal cells that surround the dorsal but not ventral evagination of the gut endoderm, which together comprise the pancreatic anlagen. To define the role of ISL1 in the development of the pancreas, we have now analysed acinar and islet cell differentiation in mice deficient in ISL1 function. Dorsal pancreatic mesenchyme does not form in ISL1-mutant embryos and there is an associated failure of exocrine cell differentiation in the dorsal but not the ventral pancreas. There is also a complete loss of differentiated islet cells. Exocrine, but not endocrine, cell differentiation in the dorsal pancreas can be rescued in vitro by provision of mesenchyme derived from wild-type embryos. These results indicate that ISL1, by virtue of its requirement for the formation of dorsal mesenchyme, is necessary for the development of the dorsal exocrine pancreas, and also that ISL1 function in pancreatic endodermal cells is required for the generation of all endocrine islet cells.

Animals↗
PubMed1996

The rat extracellular superoxide dismutase dimer is converted to a tetramer by the exchange of a single amino acid.

Extracellular superoxide dismutase (EC-SOD) is a secreted Cu and Zn-containing glycoprotein. While EC-SOD from most mammals is tetrameric and has a high affinity for heparin and heparan sulfate, rat EC-SOD has a low affinity for heparin, does not bind to heparan sulfate in vivo, and is apparently dimeric. To examine the molecular basis of the deviant physical properties of rat EC-SOD, the cDNAs of the rat and mouse EC-SODs were isolated and the deduced amino acid sequences were compared with that of human EC-SOD. Comparison of the sequences offered no obvious explanation of the differences. Analysis of a series of chimeric and point mutated EC-SODs showed that the N-terminal region contributes to the oligomeric state of the EC-SODs, and that a single amino acid, a valine (human amino acid position 24), is essential for the tetramerization. This residue is replaced by an aspartate in the rat. Rat EC-SOD carrying an Asp --> Val mutation is tetrameric and has a high heparin affinity, while mouse EC-SOD with a Val --> Asp mutation is dimeric and has lost its high heparin affinity. Thus, the rat EC-SOD dimer is converted to a tetramer by the exchange of a single amino acid. Furthermore, the cooperative action of four heparin-binding domains is necessary for high heparin affinity. These results also suggest that tetrameric EC-SODs are not symmetrical tetrahedrons, but composed of two interacting dimers, further supporting an evolutionary relationship with the dimeric cytosolic Cu and Zn-containing SODs.

Amino Acid Sequence↗
PubMed1996

Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation.

Motor neuron differentiation is accompanied by the expression of a LIM homeodomain transcription factor, Islet1 (ISL1). To assess the involvement of ISL1 in the generation of motor neurons, we analyzed cell differentiation in the neural tube of embryos in which ISL1 expression has been eliminated by gene targeting. Motor neurons are not generated without ISL1, although many other aspects of cell differentiation in the neural tube occur normally. A population of interneurons that express Engrailed1 (EN1), however, also fails to differentiate in Isl1 mutant embryos. The differentiation of EN1+ interneurons can be induced in both wild-type and mutant neural tissue by regions of the neural tube that contain motor neurons. These results show that ISL1 is required for the generation of motor neurons and suggest that motor neuron generation is required for the subsequent differentiation of certain interneurons.

Animals↗
PubMed1996

The effect of antimicrobial therapy on periimplantitis lesions. An experimental study in the dog.

The objective of the present study was to evaluate the effect of systemic antibiotics and local debridement in the treatment of experimentally induced periimplantitis lesions. 5 Labrador dogs, and about 1-year old, were included in the study. In order to establish bilateral recipient sites for implants the mandibular right and left 1st molars, 4th and 3rd premolars were removed. 6 titanium fixtures (Brånemark System Nobelpharma AB, Göteborg, Sweden) were installed and standard abutments were connected 3 months after fixture installation. Cotton floss ligatures were placed in a submarginal position around the neck of the abutments and the animals were placed on a diet which allowed plaque accumulation. After 6-8 weeks, when the tissue destruction amounted to about 20% of the fixture length, the ligatures were removed. 1 month after ligature removal, an antibiotic regimen (amoxicillin and metronidazole) was initiated and maintained for 3 weeks. In the left side of the mandible, buccal and lingual mucoperiosteal flaps were elevated, the granulation tissue within the bone craters adjacent to the implants was curetted, and the abutments were removed. The exposed outer surface, the internal part of the fixtures, as well as the abutments were treated with a detergent, delmopinol. The cleaned abutments were autoclaved, and connected to the clean fixtures. The mucoperiosteal flaps were replaced to their original position, adapted to the abutments and sutured. A careful plaque control program was initiated for the left jaw quadrants. In the right side of the mandible no local treatment was given to the fixtures and the abutments following ligature removal. Furthermore, no plaque control was provided to the implant segments in the right jaws. After 4 months of healing block biopsies including one implant with adjacent hard and soft tissue were harvested and prepared for light microscopy. It was observed that systemic antimicrobial therapy, combined with implant cleaning, curettage of the bone defect and regular plaque control resulted in (i) resolution of the periimplantitis lesion, (ii) a significant recession of the marginal periimplant mucosa, and (iii) a minor additional apical shift of the base of the bone defect. In the untreated sites the plaque associated infiltrate remained and was in several sites examined in contact with the adjacent bone tissue.

Amoxicillin↗
PubMed1995

Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia.

Extracellular superoxide dismutase (EC-SOD; superoxide:superoxide oxidoreductase, EC 1.15.1.1) is a secreted Cu- and Zn-containing tetrameric glycoprotein, the bulk of which is bound to heparan sulfate proteoglycans in the interstitium of tissues. To test the function of EC-SOD in vivo, mice carrying a targeted disruption of the EC-SOD gene were generated. The EC-SOD null mutant mice develop normally and remain healthy until at least 14 months of age. No compensatory induction of other SOD isoenzymes or other antioxidant enzymes was observed. When stressed by exposure to > 99% oxygen, the EC-SOD null mutant mice display a considerable reduction in survival time compared to wild-type mice and an earlier onset of severe lung edema. These findings suggest that while under normal physiological conditions other antioxidant systems may substitute for the loss of EC-SOD; when the animal is stressed these systems are unable to provide adequate protection.

Animals↗
PubMed1995

Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube.

The vertebrate hedgehog-related gene Sonic hedgehog (Shh) is expressed in ventral domains along the entire rostrocaudal length of the neural tube, including the forebrain. We show here that SHH induces the differentiation of ventral neuronal cell types in explants derived from prospective forebrain regions of the neural plate. Neurons induced in explants derived from both diencephalic and telencephalic levels of the neural plate express the LIM homeodomain protein Isl-1, and these neurons possess distinct identities that match those of the ventral neurons generated in these two subdivisions of the forebrain in vivo. A single inducing molecule, SHH, therefore appears to mediate the induction of distinct ventral neuronal cell types along the entire rostrocaudal extent of the embryonic central nervous system.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1995

Motoneuron fate specification revealed by patterned LIM homeobox gene expression in embryonic zebrafish.

In zebrafish, individual primary motoneurons can be uniquely identified by their characteristic cell body positions and axonal projection patterns. The fate of individual primary motoneurons remains plastic until just prior to axogenesis when they become committed to particular identities. We find that distinct primary motoneurons express particular combinations of LIM homeobox genes. Expression precedes axogenesis as well as commitment, suggesting that LIM homeobox genes may contribute to the specification of motoneuronal fates. By transplanting them to new spinal cord positions, we demonstrate that primary motoneurons can initiate a new program of LIM homeobox gene expression, as well as the morphological features appropriate for the new position. We conclude that the patterned distribution of different primary motoneuronal types within the zebrafish spinal cord follows the patterned expression of LIM homeobox genes, and that this reflects a highly resolved system of positional information controlling gene transcription.

Amino Acid Sequence↗
PubMed1995

IPF1, a homeodomain protein with a dual function in pancreas development.

Insulin promoter factor 1 (IPF1), is a homeodomain protein which, in the adult mouse pancreas, is selectively expressed in beta-cells, and which binds to, and transactivates, the insulin promoter via the P1 element. In mouse embryos, IPF1 expression is initiated when the foregut endoderm commits to a pancreatic fate, i.e. prior to both morphogenesis and hormone specific gene expression. At later stages of development the expression is restricted to the dorsal and ventral walls of the primitive foregut at the positions where the pancreases will form. Mice homozygous for a targeted mutation in the Ipf1 gene selectively lack the pancreas. The mutant pups develop to term and are born alive, but die after a few days. The gastrointestinal tract with its associated organs show no obvious malformations. No pancreatic tissue and no ectopic expression of insulin or pancreatic amylase could be detected in this region in mutant neonates or embryos. These findings demonstrate that IPF1 is needed for the formation of the pancreas, and suggest that IPF1 acts to determine the fate of common pancreatic precursor cells and/or to regulate their propagation. The lack of a pancreas in the Ipf1-deficient mutants, the pattern of IPF1 expression and its ability to stimulate insulin gene transcription, strongly suggest that IPF1 functions both in the early specification of the primitive gut to a pancreatic fate and in the maturation of the pancreatic beta-cell.

Aging↗
PubMed1995

Sonic hedgehog: a common signal for ventral patterning along the rostrocaudal axis of the neural tube.

The vertebrate hedgehog-related gene, sonic hedgehog, is expressed in ventral domains along the entire rostrocaudal length of the neural tube, including the forebrain. Shh induces the differentiation of ventral neuronal cell types in explants derived from prospective forebrain regions of the neural plate. Neurons induced in explants derived from diencephalic and telencephalic levels of the neural plate express the LIM homeodomain protein Islet-1, but these neurons possess distinct identities that match those of the ventral neurons normally generated in these two subdivisions of the forebrain. These results, together with other studies of neuronal differentiation at caudal levels of the neural tube, suggest that a single inducing molecule, Shh, mediates the induction of distinct ventral neuronal cell types along the entire rostrocaudal extent of the embryonic central nervous system.

Animals↗
PubMed1994

Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes.

Motor neurons located at different positions in the embryonic spinal cord innervate distinct targets in the periphery, establishing a topographic neural map. The topographic organization of motor projections depends on the generation of subclasses of motor neurons that select specific paths to their targets. We have cloned a family of LIM homeobox genes in chick and show here that the combinatorial expression of four of these genes, Islet-1, Islet-2, Lim-1, and Lim-3, defines subclasses of motor neurons that segregate into columns in the spinal cord and select distinct axonal pathways. These genes are expressed prior to the formation of distinct motor axon pathways and before motor columns appear. Our results suggest that LIM homeobox genes contribute to the generation of motor neuron diversity and may confer subclasses of motor neurons with the ability to select specific axon pathways, thereby initiating the topographic organization of motor projections.

Afferent Pathways↗
PubMed1994

Insulin-promoter-factor 1 is required for pancreas development in mice.

The mammalian pancreas is a mixed exocrine and endocrine gland that, in most species, arises from ventral and dorsal buds which subsequently merge to form the pancreas. In both mouse and rat the first histological sign of morphogenesis of the dorsal pancreas is a dorsal evagination of the duodenum at the level of the liver at around the 22-25-somite stage, and shortly thereafter a ventral evagination appears as a derivative of the liver diverticulum. Low levels of insulin gene transcripts are already present and restricted to the dorsal foregut endoderm at 20 somites, suggesting that pancreas- or insulin gene-specific transcriptional factors are present in this region before the onset of morphogenesis. Insulin-promoter-factor 1 (IPF1) is a homeodomain protein which, in the adult mouse pancreas, is selectively expressed in the beta-cells and binds to and transactivates the insulin promoter. In mouse embryos, IPF1 expression is restricted to the developing pancreatic anlagen and is initiated when the foregut endoderm is committed to a pancreatic fate. We now show that mice homozygous for a targeted mutation in the Ipf1 gene selectively lack a pancreas. The mutant pups survive fetal development but die within a few days after birth. The gastrointestinal part and all other internal organs were normal in appearance. No pancreatic tissue and no ectopic expression of insulin or pancreatic amylase could be detected in mutant embryos and neonates. These findings show that IPF1 is needed for the formation of the pancreas and suggest that it acts to determine the fate of common pancreatic precursor cells and/or to regulate their propagation.

Animals↗
PubMed1994

Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord.

The differentiation of distinct cell types in the ventral neural tube depends on local inductive signals from the notochord. We have isolated a vertebrate homolog of the Drosophila segment polarity gene hedgehog (hh) from zebrafish and rat, termed vhh-1. vhh-1 is expressed in the node, notochord, floor plate, and posterior limb bud mesenchyme. Each of these cell groups has floor plate inducing activity, suggesting that the vhh-1 gene may encode a floor plate-inducing molecule. Widespread expression of rat vhh-1 in frog embryos leads to ectopic floor plate differentiation in the neural tube. In vitro tests for the signaling functions of vhh-1 demonstrate that COS cells expressing the rat vhh-1 gene induce floor plate and motor neuron differentiation in neural plate explants. vhh-1 may, therefore, contribute to the floor plate and motor neuron inducing activities of the notochord.

Amino Acid Sequence↗
PubMed1993

Heparin-affinity patterns and composition of extracellular superoxide dismutase in human plasma and tissues.

The tetrameric extracellular superoxide dismutase (EC-SOD) in human tissues and plasma has previously been found to be heterogenous with regard to heparin affinity and could be divided into at least three classes: A, lacking heparin affinity; B, with weak affinity; and C, with strong affinity. Using rigorous extraction conditions and an extensive set of anti-proteolytic agents, tissue EC-SOD is now shown to be almost exclusively of native homotetrameric C-class. Plasma EC-SOD on the other hand is shown to be mainly composed of a complex mixture of heterotetramers with modifications probably residing in the C-terminal heparin-binding domain. Proteolytic truncations appear to be a major cause of this heterogeneity. The findings suggest that, since 99% of the EC-SOD in the human body exists in the extravascular space of tissue, EC-SOD is primarily synthesized in tissues and secreted as homotetrameric native EC-SOD C. This tissue EC-SOD C should exist almost completely sequestered by heparin sulphate proteoglycans. C-terminal modifications subsequently occurring in the EC-SOD C would weaken the binding to heparan sulphate proteoglycan, facilitate entrance to the vasculature through capillaries and lymph flow, and finally result in the heterogeneous plasma EC-SOD pattern. With the new extraction and analysis procedure, the tissue content of EC-SOD is found to be higher than previously reported. It is found, for example, when compared with Mn-SOD, to be higher in umbilical cord and uterus, about equal in placenta and testis and as high as that of CuZn-SOD in umbilical cord. The findings suggest that the protection level against superoxide radicals provided by EC-SOD in the tissue interstitial space, given the small distribution volume, is not much less prominent than that bestowed on the intracellular space by CuZn-SOD and Mn-SOD.

Blotting, Western↗
PubMed1993

Control of cell pattern in the neural tube: motor neuron induction by diffusible factors from notochord and floor plate.

The identity of cell types generated along the dorsoventral axis of the neural tube depends on inductive signals that derive from both mesodermal and neural cells. To define the nature of these signals, we have analyzed the differentiation of cells in neural plate explants. Motor neurons and neural crest cells differentiate in vitro from appropriate regions of the neural plate, indicating that the specification of cell fate along the dorsoventral axis of the neural tube begins at the neural plate stage. Motor neuron differentiation can be induced by a diffusible factor that derives initially from the notochord and later from floor plate cells. By contrast, floor plate induction requires contact with the notochord. Thus, the identity and patterning of neural cell types appear to involve distinct contact-mediated and diffusible signals from the notochord and floor plate.

Animals↗
PubMed1993

Control of cell pattern in the neural tube: regulation of cell differentiation by dorsalin-1, a novel TGF beta family member.

Distinct cell types differentiate along the dorsoventral axis of the neural tube. We have cloned and characterized a novel member of the TGF beta gene family, dorsalin-1 (dsl-1), that appears to regulate cell differentiation within the neural tube. dsl-1 is expressed selectively in the dorsal neural tube, and its pattern of expression appears to be restricted by early signals from the notochord. Exposure of neural plate cells to dsl-1 promotes the differentiation of cells with neural crest-like properties and inhibits the induction of motor neurons by signals from the notochord and floor plate. These findings suggest that dsl-1 regulates the differentiation of cell types along the dorsoventral axis of the neural tube, acting in conjunction with distinct ventralizing signals from the notochord and floor plate.

Amino Acid Sequence↗
PubMed1993

IPF1, a homeodomain-containing transactivator of the insulin gene.

We describe the cloning of insulin promoter factor 1 (IPF1), a homeodomain protein which in the adult mouse pancreas is selectively expressed in the beta-cells and which binds to and transactivates the insulin promoter. In embryos, IPF1 expression is initiated prior to hormone gene expression and is restricted to the dorsal and ventral walls of the primitive foregut at the positions where pancreas will later form. The pattern of IPF1 expression and its ability to stimulate insulin gene transcription suggest that IPF1 functions both in the regionalization of the primitive gut endoderm and in the maturation of the pancreatic beta-cell.

Amino Acid Sequence↗
PubMed1993

Pharmacokinetics of extracellular-superoxide dismutase in the vascular system.

Extracellular-superoxide dismutase C (EC-SOD C) is a secretory tetrameric Cu- and Zn-containing glycoprotein which has high affinity for heparin and heparan sulfate. Upon intravenous injection into rabbits, recombinant human (rh) EC-SOD C was found to be rapidly 97-98% sequestered to the vascular wall, forming an equilibrium with the plasma phase. Recombinant EC-SOD truncation variants with reduced, T216, and without, T213, heparin affinity were found to be sequestered to a reduced extent and not at all, respectively, establishing the importance of the heparin affinity for this behaviour. The halflife of rhEC-SOD C in the vasculature was of the order of 20 h. Injection of large doses resulted in saturation of the binding of rhEC-SOD C to the vascular wall. Scatchard analysis revealed a heterogeneity in affinity of the ligands on the vascular wall. The maximal binding capacity was very high. The equilibration of rhEC-SOD C to the vascular wall of an organ, clamped during enzyme injection, and the primary equilibration phase was studied by comparing binding to a clamped and reperfused kidney with binding to the contralateral control kidney. rhEC-SOD C injected in a low dose was found to equilibrate very slowly to the reperfused kidney with a halftime of about 2 h. With higher rhEC-SOD C doses, at which evidence for saturation is seen, and with the variant rhEC-SOD with reduced heparin affinity. T216, very rapid equilibrations were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗