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C Birchmeier

Publications and source records attributed to C Birchmeier.

At least 37 records · Page 2Linked to original sources
PubMed1998

Sustained long term potentiation and anxiety in mice lacking the Mas protooncogene.

The Mas protooncogene is a maternally imprinted gene encoding an orphan G protein-coupled receptor expressed mainly in forebrain and testis. Here, we provide evidence for a function of Mas in the central nervous system. Targeted disruption of the Mas protooncogene leads to an increased durability of long term potentiation in the dentate gyrus, without affecting hippocampal morphology, basal synaptic transmission, and presynaptic function. In addition, Mas-/- mice show alterations in the onset of depotentiation. The permissive influence of Mas ablation on hippocampal synaptic plasticity is paralleled by behavioral changes. While spatial learning in the Morris water maze is not significantly influenced, Mas-deficient animals display an increased anxiety as assessed in the elevated-plus maze. Thus, Mas is an important modulating factor in the electrophysiology of the hippocampus and is involved in behavioral pathways in the adult brain.

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PubMed1998

Engineered mutants of HGF/SF with reduced binding to heparan sulphate proteoglycans, decreased clearance and enhanced activity in vivo.

BACKGROUND: Although a number of growth factors bind cell-surface heparan sulphate proteoglycans (HSPGs), the role of this interaction is unclear except for fibroblast growth factor which requires HSPG binding for signalling. Hepatocyte growth factor/scatter factor (HGF/SF) plays important roles in mammalian development and tissue regeneration and acts on target cells through a specific receptor tyrosine kinase encoded by the c-met proto-oncogene. This factor also binds HSPGs with high affinity, but conflicting data have been reported on the role of HSPG binding in HGF/SF signalling. RESULTS: To map the binding sites for HSPG and the Met receptor in HGF/SF, we have engineered a number of HGF/SF mutants in which several clusters of solvent-accessible residues in the hairpin structure of the amino-terminal domain or in kringle 2 have been replaced. Two of the mutants (HP1 and HP2) showed greatly decreased (more than 50-fold) affinity for heparin and HSPGs but retained full mitogenic and motogenic activities on target cells in culture. Furthermore, when compared with wild-type HGF/SF, the HP1 mutant exhibited a delayed clearance from the blood, higher tissue levels and a higher induction of DNA synthesis in normal, adult murine liver. CONCLUSIONS: These results establish the following: the binding sites in HGF/SF for Met and for HSPGs can be dissociated by protein engineering; high-affinity binding of HGF/SF to HSPGs is not essential for signalling; one role of HSPG binding in the HGF/SF system appears to be sequestration and degradation of the growth factor; and HGF/SF mutants with decreased affinity for HSPGs exhibit enhanced activity in vivo.

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PubMed1998

Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase.

A number of developmental processes that involve cell migration, growth or morphogenesis depend on extracellular signals. A molecule that provides such signals, known as hepatocyte growth factor/scatter factor (HGF/SF), has attracted considerable interest in recent years because of its distinct structure, mechanism of activation and important roles throughout embryogenesis. This review discusses the main features of HGF/SF and its receptor, the product of the c-met protooncogene, and their role in embryogenesis.

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PubMed1997

Severe neuropathies in mice with targeted mutations in the ErbB3 receptor.

Neuregulins and their specific receptors, members of the ErbB family of tyrosine kinases, have been implicated in the control of growth and development of Schwann cells, specialized cells that wrap around nerve axons to provide electrical insulation. Here we use gene targeting to generate mice that lack ErbB3, a high-affinity neuregulin receptor. Homozygous erbB3 mutant embryos lack Schwann-cell precursors and Schwann cells that accompany peripheral axons of sensory and motor neurons. The initial development of motor neurons and sensory neurons of dorsal root ganglia occurs as it should, but at later stages most motor neurons (79%) and sensory neurons in dorsal root ganglia (82%) undergo cell death in erbB3 mutant embryos. Degeneration of the peripheral nervous system in erbB3 mutant pups is thus much more severe than the cell death in mice that lack neurotrophins or neurotrophin receptors. We also show that ErbB3 functions in a cell-autonomous way during the development of Schwann cells, but not in the survival of sensory or motor neurons. Our results indicate that sensory and motor neurons require factors for their survival that are provided by developing Schwann cells.

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PubMed1997

The functions of HGF/SF and its receptor, the c-Met tyrosine kinase, in mammalian development.

Hepatocyte growth factor/scatter factor (HGF/SF) can induce epithelial-mesenchymal conversion of epithelial cells in culture, with the dissociated cells becoming highly motile. The signal given by HGF/SF is mediated by its specific receptor, the c-Met tyrosine kinase. Targeted mutations in the mouse have demonstrated that HGF/SF and c-Met take over functions in development of the placenta, liver and skeletal muscle. During development of skeletal muscle, the receptor and its ligand control migration of myogenic precursor cells in the embryo. These myogenic precursors undergo an epithelial-mesenchymal conversion and detach from the dermomyotome of the somite. They then migrate to different sites in the embryo where they terminally differentiate to form skeletal muscle. Mutations in the HGF/SF or c-met genes abolish emigration of myogenic precursor cells. As a consequence, skeletal muscle groups that derive from migrating cells do not form. Ectopic application of HGF/SF in the chick embryo induces epithelial-mesenchymal conversion and emigration of dermomyotomal cells. Moreover, the expression patterns of HGF/SF and c-Met in the mouse embryo are in accordance with a function of HGF/SF in the induction of epithelial-mesenchymal conversion and the generation of migrating myogenic precursor cells in vivo. The pattern suggests additional roles during the migratory process, which will be discussed.

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PubMed1997

Met -/- kidneys express epithelial cells that chemotax and form tubules in response to EGF receptor ligands.

The growth factor/receptor combination of hepatocyte growth factor (HGF)/c-met has been postulated to be critical for mesenchymal-to-epithelial conversion and tubule formation in the developing kidney. We therefore isolated and immortalized cells from embryonic kidneys of met -/- transgenic mice to determine whether these cells were epithelial and able to chemotax and form tubules in vitro. The cells were immortalized with retrovirus expressing human papillomavirus 16 (HPV 16) E6/E7 genes. Two rapidly dividing clones were isolated and found to express the epithelial cell markers cytokeratin, zonula occludens-1, and E-cadherin but not to express the fibroblast marker vimentin. The met -/- cells were able to chemotax in response to epidermal growth factor and transforming growth factor-alpha (TGF-alpha) and form tubules in vitro in response to TGF-alpha but not HGF. These experiments suggest that the HGF/c-met axis is not essential for epithelial cell development in the embryonic kidney and demonstrate that other growth factors are capable of supporting early tubulogenesis.

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PubMed1997

Isoform-specific expression and function of neuregulin.

Neuregulin (also known as NDF, heregulin, ARIA, GGF or SMDF), induces cell growth and differentiation. Biological effects of neuregulin are mediated by members of the erbB family of tyrosine kinase receptors. Three major neuregulin isoforms are produced from the gene, which differ substantially in sequence and in overall structure. Here we use in situ hybridization with isoform-specific probes to illustrate the spatially distinct patterns of expression of the isoforms during mouse development. Ablation of the neuregulin gene in the mouse has demonstrated multiple and independent functions of this factor in development of both the nervous system and the heart. We show here that targeted mutations that affect different isoforms result in distinct phenotypes, demonstrating that isoforms can take over specific functions in vivo. Type I neuregulin is required for generation of neural crest-derived neurons in cranial ganglia and for trabeculation of the heart ventricle, whereas type III neuregulin plays an important role in the early development of Schwann cells. The complexity of neuregulin functions in development is therefore due to independent roles played by distinct isoforms.

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PubMed1996

Scatter factor/hepatocyte growth factor (SF/HGF) induces emigration of myogenic cells at interlimb level in vivo.

The initiating event in the migration of myogenic cells to the limb buds is an epitheliomesenchymal transformation of cells located at the lateral edge of the dermomyotome. Recently, a targeted mutation of c-met in mice demonstrated an essential role of this tyrosine kinase receptor and its ligand, scatter factor/hepatocyte growth factor (SF/HGF), in the migration of myogenic cells to the limb buds. Here, we show that ectopic application of exogenous SF/HGF induces emigration of Pax-3-positive myogenic cells into the lateral plate mesoderm. During this process, the lateral portions of the dermomyotomes deepithelialize and the basement membrane disintegrates. Detaching myogenic cells do not lose N-cadherin from their surfaces. We conclude that an HGF/SF- and c-met-mediated signal detaches myogenic precursor cells from the somites and thus plays a necessary role in the initiation of myoblast migration.

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PubMed1996

The c-ros tyrosine kinase receptor controls regionalization and differentiation of epithelial cells in the epididymis.

The c-ros gene was originally identified in mutant form as an oncogene. The proto-oncogene encodes a tyrosine kinase receptor that is expressed in a small number of epithelial cell types, including those of the epididymis. Targeted mutations of c-ros in the mouse reveal an essential role of the gene in male fertility. Male c-ros -/- animals do not reproduce, whereas the fertility of female animals is not affected. We demonstrate that c-ros is not required in a cell autonomous manner for male germ cell development or function. The gene, therefore, does not affect sperm generation or function in a direct manner. The primary defect in the mutant animals was located in the epididymis, showing that c-ros controls appropriate development of the epithelia, particularly regionalization and terminal differentiation. The epididymal defect does not interfere with production or storage of sperm but, rather, with sperm maturation and the ability of sperm to fertilize in vivo. Interestingly, sperm isolated from c-ros -/- animals can fertilize in vitro. Our results highlight the essential role of the epididymis in male fertility and demonstrate a highly specific function of the c-ros receptor tyrosine kinase during development of distinct epithelial cells.

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PubMed1996

Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons.

In the embryonic nervous system, developing axons can be guided to their targets by diffusible factors secreted by their intermediate and final cellular targets. To date only one family of chemoattractants for developing axons has been identified. Grafting and ablation experiments in fish, amphibians, and birds have suggested that spinal motor axons are guided to their targets in the limb in part by a succession of chemoattractants made by the sclerotome and by the limb mesenchyme, two intermediate targets that these axons encounter en route to their target muscles. Here we identify the limb mesenchyme-derived chemoattractant as hepatocyte growth factor/scatter factor (HGF/SF), a diffusible ligand for the c-Met receptor tyrosine kinase, and we also implicate HGF/SF at later stages as a muscle-derived survival factor for motoneurons. These results indicate that, in addition to functioning as a mitogen, a motogen, and a morphogen in nonneural systems, HGF/SF can function as a guidance and survival factor in the developing nervous system.

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PubMed1996

Targeted mutation of plakoglobin in mice reveals essential functions of desmosomes in the embryonic heart.

Plakoglobin (gamma-catenin), a member of the armadillo family of proteins, is a constituent of the cytoplasmic plaque of desmosomes as well as of other adhering cell junctions, and is involved in anchorage of cytoskeletal filaments to specific cadherins. We have generated a null mutation of the plakoglobin gene in mice. Homozygous -/- mutant animals die between days 12-16 of embryogenesis due to defects in heart function. Often, heart ventricles burst and blood floods the pericard. This tissue instability correlates with the absence of desmosomes in heart, but not in epithelia organs. Instead, extended adherens junctions are formed in the heart, which contain desmosomal proteins, i.e., desmoplakin. Thus, plakoglobin is an essential component of myocardiac desmosomes and seems to play a crucial role in the sorting out of desmosomal and adherens junction components, and consequently in the architecture of intercalated discs and the stabilization of heart tissue.

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PubMed1996

Epithelial-mesenchymal transitions in cancer progression.

Epithelial cells are the most important cell type in the development of human malignancies. More than 90% of all malignant tumors are carcinomas, and thus of epithelial origin. Aberrant growth and the ability to invade the underlying tissues are intrinsic properties of the fatally altered cells. Multiple genetic alterations that can influence growth and genetic stability of the carcinoma cells have been characterised during tumor progression. Loss of epithelial morphology and the acquisition of mesenchymal characteristics are typical for carcinoma cells late in tumor progression and correlate with metastatic potential. In vitro, epithelial-mesenchymal transitions can be induced by interference with the integrity of the adherens junction, by signalling via tyrosine kinases, and by oncogene expression. In carcinoma cells, loss or downregulation of E-cadherin expression are frequently observed in carcinomas, and correlate with the malignancy of the tumor. In general, this change in expression is regulated at the transcriptional level. However, tumor types or cell lines exist which show mesenchymal characteristics but nevertheless express E-cadherin protein or mRNA. A more-detailed analysis demonstrated that other mechanisms that interfere with E-cadherin-mediated cell adhesion can be operative. Mutations in the E-cadherin gene and loss or mutation of the second, intact copy as well as mutation in the catenin genes, which encode proteins that interact with the cytoplasmic portion of E-cadherin, can be observed. In addition, transient or unregulated phosphorylation by receptor tyrosine kinases or oncogenic tyrosine kinases, respectively, can interfere with the epithelial morphology and induce a mesenchymal conversion. Since tyrosine phosphorylation of beta-catenin correlates with the epithelial-mesenchymal transition that is observed, E-cadherin-mediated cell adhesion might be modulated by such a mechanism. Interestingly, the same molecules implicated in the control of malignant properties turn out to play fundamental roles in the control of normal epithelial growth, differentiation and morphogenesis.

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PubMed1995

Multiple essential functions of neuregulin in development.

Neuregulin (also called NDF, heregulin, GGF and ARIA) is a member of the EGF family which induces growth and differentiation of epithelial, glial and muscle cells in culture. The biological effects of the factor are mediated by tyrosine kinase receptors. Neuregulin can bind directly to erbB3 and erbB4 and receptor heterodimerization allows neuregulin-dependent activation of erbB2 (refs 1, 2, 5). A targeted mutation in mice reveals multiple essential roles of neuregulin in development. Here we show that neuregulin -/- embryos die during embryogenesis and display heart malformations. In addition, Schwann cell precursors and cranial ganglia fail to develop normally. The phenotype demonstrates that in vivo neuregulin acts locally and frequently in a paracrine manner. All cell types affected by the mutation express either erbB3 or erbB4, indicating that either of these tyrosine kinase receptors can be a component in recognition and transmission of essential neuregulin signals.

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PubMed1995

Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud.

Limb muscles develop from cells that migrate from the somites. The signal that induces migration of myogenic precursor cells to the limb emanates from the mesenchyme of the limb bud. Here we report that the c-met-encoded receptor tyrosine kinase is essential for migration of myogenic precursor cells into the limb anlage and for migration into diaphragm and tip of tongue. In c-met homozygous mutant (-/-) mouse embryos, the limb bud and diaphragm are not colonized by myogenic precursor cells and, as a consequence, skeletal muscles of the limb and diaphragm do not form. In contrast, development of the axial skeletal muscles proceeds in the absence of c-met signalling. The specific ligand of the c-met protein, the motility and growth factor scatter factor/hepatocyte growth factor, is expressed in limb mesenchyme and can thus provide the signal for migration which is received by c-met. We have therefore identified a paracrine signalling system that regulates migration of myogenic precursor cells.

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PubMed1995

Scatter factor/hepatocyte growth factor is essential for liver development.

Polypeptide growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor/hepatocyte growth factor (SF/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood proteinase plasminogen. The cellular responses of SF/HGF are mediated by the c-Met tyrosine kinase receptor. Here we report that mice lacking SF/HGF fail to complete development and die in utero. The mutation affects the embryonic liver, which is reduced in size and shows extensive loss of parenchymal cells. In addition, development of the placenta, particularly of trophoblast cells, is impaired. Thus, SF/HGF is essential for the development of several epithelial organs.

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PubMed1995

A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development.

The Ca(2+)-dependent cell adhesion molecule E-cadherin functions in the establishment and maintenance of epithelial cell morphology during embryogenesis and adulthood. Downregulation or complete shut-down of E-cadherin expression and mutation of the gene are observed during the progression of tumors of epithelial origin (carcinomas) and correlate with the metastatic potential. We have introduced a targeted mutation into the E-cadherin gene by homologous recombination in mouse embryonic stem cells. The mutation removes E-cadherin sequences essential for Ca2+ binding and for adhesive function. These embryonic stem cells were used to generate mice carrying the mutation. Heterozygous mutant animals appear normal and are fertile. However, the homozygous mutation is not compatible with life: E-cadherin -/- embryos show severe abnormalities before implantation. Particularly, the adhesive cells of the morula dissociate shortly after compaction has occurred, and their morphological polarization is then destroyed. Interestingly, the blastomers are still able to form desmosomes and tight junctions at sites of distorted cell-cell contact. Thus, maternal E-cadherin suffices for initial compaction of the morula but not for further preimplantation development to occur.

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PubMed1995

Epithelial-mesenchymal transitions in development and tumor progression.

Epithelial-mesenchymal transitions play important roles in development and malignancy. Here we discuss molecular events in the control of such transitions: changes in cellular adhesion components, action of oncogenes and tyrosine kinase receptors, as well as activation of transcription factors. In development, epithelial-mesenchymal transitions take place in a temporally and spatially controlled manner, whereas in tumors these changes are highly uncontrolled. Loss of epithelial character is typically observed late in progression of human carcinomas, and correlates there with the acquisition of invasive and metastatic potential.

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