| 1. |
- Moser, Markus, et al.
(author)
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Ultrastructural cartilage abnormalities in MIA/CD-RAP-deficient mice
- 2002
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In: Molecular and Cellular Biology. - 0270-7306. ; 22:5, s. 1438-1445
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Journal article (peer-reviewed)abstract
- MIA/CD-RAP is a small, soluble protein secreted from malignant melanoma cells and from chondrocytes. Recent evidence has identified MIA/CD-RAP as the prototype of a small family of extracellular proteins adopting an SH3 domain-like fold. It is thought that interaction between MIA/CD-RAP and specific epitopes in extracellular matrix proteins regulates the attachment of tumor cells and chondrocytes. In order to study the consequences of MIA/CD-RAP deficiency in vivo, we generated mice with a targeted gene disruption. The complete absence of MIA/CD-RAP mRNA and protein expression was demonstrated by reverse transcriptase, Western blot analysis, and enzyme-linked immunosorbent assay measurements of whole-embryo extracts. MIA-/- mice were viable and developed normally, and histological examination of the organs by means of light microscopy revealed no major abnormalities. In contrast, electron microscopic studies of cartilage composition revealed subtle defects in collagen fiber density, diameter, and arrangement, as well as changes in the number and morphology of chondrocytic microvilli. Taken together, our data indicate that MIA/CD-RAP is essentially required for formation of the highly ordered ultrastructural fiber architecture in cartilage and may have a role in regulating chondrocyte matrix interactions.
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| 2. |
- Zhou, Xiao-Hong, et al.
(author)
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Neurocan is dispensable for brain development
- 2001
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In: Molecular and Cellular Biology. - 0270-7306. ; 21:17, s. 5970-5978
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Journal article (peer-reviewed)abstract
- Neurocan is a component of the extracellular matrix in brain. Due to its inhibition of neuronal adhesion and outgrowth in vitro and its expression pattern in vivo it was suggested to play an important role in axon guidance and neurite growth. To study the role of neurocan in brain development we generated neurocan-deficient mice by targeted disruption of the neurocan gene. These mice are viable and fertile and have no obvious deficits in reproduction and general performance. Brain anatomy, morphology, and ultrastructure are similar to those of wild-type mice. Perineuronal nets surrounding neurons appear largely normal. Mild deficits in synaptic plasticity may exist, as maintenance of late-phase hippocampal long-term potentiation is reduced. These data indicate that neurocan has either a redundant or a more subtle function in the development of the brain.
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| 3. |
- Bengtsson, T, et al.
(author)
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Loss of alpha 10 beta 1 integrin expression leads to moderate dysfunction of growth plate chondrocytes
- 2005
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In: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 118:5, s. 929-936
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Journal article (peer-reviewed)abstract
- Integrin alpha 10 beta 1 is a collagen-binding integrin expressed on chondrocytes. In order to unravel the role of the alpha 10 integrin during development, we generated mice carrying a constitutive deletion of the alpha 10 integrin gene. The mutant mice had a normal lifespan and were fertile but developed a growth retardation of the long bones. Analysis of the skeleton revealed defects in the growth plate after birth characterized by a disturbed columnar arrangement of chondrocytes, abnormal chondrocyte shape and reduced chondrocyte proliferation. Electron microscopy of growth plates from newborn mice revealed an increased number of apoptotic chondrocytes and reduced density of the collagen fibrillar network compared to these structures in control mice. These results demonstrate that integrin alpha 10 beta 1 plays a specific role in growth plate morphogenesis and function.
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| 4. |
- Brakebusch, Cord, et al.
(author)
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Beta1 integrin is not essential for hematopoiesis but is necessary for the T cell-dependent IgM antibody response.
- 2002
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In: Immunity. - 1074-7613. ; 16:3, s. 465-477
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Journal article (peer-reviewed)abstract
- Several experimental evidences suggested that beta1 integrin-mediated adhesion of hematopoietic stem cells (HSC) is important for their function in the bone marrow (BM). Using induced deletion of the beta1 integrin gene restricted to the hematopoietic system, we show that beta1 integrin is not essential for HSC retention in the BM, hematopoiesis, and trafficking of lymphocytes. However, immunization with a T cell-dependent antigen resulted in virtually no IgM production and an increased secretion of IgG in mutant mice, while the response to a T cell-independent type 2 antigen showed decreases in both IgM and IgG. These data suggest that beta1 integrins are necessary for the primary IgM antibody response.
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| 5. |
- Brakebusch, Cord, et al.
(author)
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Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory
- 2002
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In: Molecular and Cellular Biology. - 0270-7306. ; 22:21, s. 7417-7427
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Journal article (peer-reviewed)abstract
- Brevican is a brain-specific proteoglycan which is found in specialized extracellular matrix structures called perineuronal nets. Brevican increases the invasiveness of glioma cells in vivo and has been suggested to play a role in central nervous system fiber tract development. To study the role of brevican in the development and function of the brain, we generated mice lacking a functional brevican gene. These mice are viable and fertile and have a normal life span. Brain anatomy was normal, although alterations in the expression of neurocan were detected. Perineuronal nets formed but appeared to be less prominent in mutant than in wild-type mice. Brevican-deficient mice showed significant deficits in the maintenance of hippocampal long-term potentiation (LTP). However, no obvious impairment of excitatory and inhibitory synaptic transmission was found, suggesting a complex cause for the LTP defect. Detailed behavioral analysis revealed no statistically significant deficits in learning and memory. These data indicate that brevican is not crucial for brain development but has restricted structural and functional roles.
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| 6. |
- Brakebusch, Cord, et al.
(author)
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Integrins in invasive growth.
- 2002
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In: Journal of Clinical Investigation. - 0021-9738. ; 109:8, s. 999-1006
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Journal article (peer-reviewed)
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| 7. |
- Brandau, Oliver, et al.
(author)
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Chondromodulin I Is Dispensable during Enchondral Ossification and Eye Development.
- 2002
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In: Molecular and Cellular Biology. - 0270-7306. ; 22:18, s. 6627-6635
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Journal article (peer-reviewed)abstract
- Chondromodulin I (chm-I), a type II transmembrane protein, is highly expressed in the avascular zones of cartilage but is downregulated in the hypertrophic region, which is invaded by blood vessels during enchondral ossification. In vitro and in vivo assays with the purified protein have shown chondrocyte-modulating and angiogenesis-inhibiting functions. To investigate chm-I function in vivo, we generated transgenic mice lacking chm-I mRNA and protein. Null mice are viable and fertile and show no morphological changes. No abnormalities in vascular invasion and cartilage development were detectable. No evidence was found for a compensating function of tendin, a recently published homologue highly expressed in tendons and also, at low levels, in cartilage. Furthermore, no differences in the expression of other angiogenic or antiangiogenic factors such as transforming growth factor beta1 (TGF-beta1), TGF-beta2, TGF-beta3, fibroblast growth factor 2, and vascular endothelial growth factor were found. The surprising lack of phenotype in the chm-I-deficient mice suggests either a different function for chm-I in vivo than has been proposed or compensatory changes in uninvestigated angiogenic or angiogenesis-inhibiting factors. Further analysis using double-knockout technology will be necessary to analyze the function of chm-I in the complex process of enchondral ossification.
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| 8. |
- Braun, Attila, et al.
(author)
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Genomic organization of profilin-III and evidence for a transcript expressed exclusively in testis.
- 2002
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In: Gene. - 1879-0038. ; 283:1-2, s. 219-225
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Journal article (peer-reviewed)abstract
- Profilins are small, widely expressed actin binding proteins, thought to be key regulators of actin dynamics in living cells. So far, three profilin-genes have been described: profilin-I (PFN1), profilin-II (PFN2) with two splice variants and the recently identified profilin-III (PFN3). Here we describe the genomic organization of the genes encoding human and mouse profilin-III. Both are single exon genes and lie in close vicinity to the renal sodium-phosphate transport gene 2 (SLC34A1, NPT2) which is highly expressed in kidney. Northern hybridization to rat tissues has previously demonstrated expression of an approximately 4.5 kb long profilin-III mRNA transcript in kidney and a mRNA transcript of approximately 1 kb in length in testis. Here we show that mouse profilin-III expression is restricted to testis and that the 4.2 kb profilin-III mRNA in kidney is the result of a slc34a1 transcript which includes the antisense profilin-III open reading frame in its 3prime prime or minute-untranslated region. Finally, we demonstrate by in situ hybridization that profilin-III mRNA is localized to cells in the late stage of spermatogenesis.
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| 9. |
- Costell, M, et al.
(author)
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Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice
- 2002
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In: Circulation Research. - 0009-7330. ; 91:2, s. 158-164
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Journal article (peer-reviewed)abstract
- Perlecan is a heparan-sulfate proteoglycan abundantly expressed in pericellular matrices and basement membranes during development. Inactivation of the perlecan gene in mice is lethal at two developmental stages: around E10 and around birth. We report a high incidence of malformations of the cardiac outflow tract in perlecan-deficient embryos. Complete transposition of great arteries was diagnosed in 11 out of 15 late embryos studied (73%). Three of these 11 embryos also showed. malformations of semilunar valves. Mesenchymal cells in the outflow tract were abnormally abundant in mutant embryos by E9.5, when the endocardial-mesenchymal transformation starts in wild-type embryos. At E10.5, mutant embryos lacked well-defined spiral endocardial ridges, and the excess of mesenchymal cells obstructed sometimes the outflow tract lumen. Most of this anomalous mesenchyme expressed the smooth muscle cell-specific a-actin isoform, a marker of the neural crest in the outflow tract of the mouse. In wild-type embryos, perlecan is present in the basal surface of myocardium and endocardium, as well as surrounding presumptive neural crest cells. We suggest that the excess of mesenchyme at the earlier stages of conotruncal development precludes the formation of the spiral ridges and the rotation of the septation complex in order to achieve a concordant ventriculoarterial connection. The observed mesenchymal overpopulation might be due to an uncontrolled migration of neural crest cells, which would arrive prematurely to the heart. Thus, perlecan is involved in the control of the outflow tract mesenchymal population size, underscoring the importance of the extracellular matrix in cardiac morphogenesis.
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| 10. |
- Costell, Mercedes, et al.
(author)
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Perlecan maintains the integrity of cartilage and some basement membranes
- 1999
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In: Journal of Cell Biology. - 0021-9525. ; 147:5, s. 1109-1122
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Journal article (peer-reviewed)abstract
- Perlecan is a heparan sulfate proteoglycan that is expressed in all basement membranes (BMs), in cartilage, and several other mesenchymal tissues during development. Perlecan binds growth factors and interacts with various extracellular matrix proteins and cell adhesion molecules. Homozygous mice with a null mutation in the perlecan gene exhibit normal formation of BMs. However, BMs deteriorate in regions with increased mechanical stress such as the contracting myocardium and the expanding brain vesicles showing that perlecan is crucial for maintaining BM integrity. As a consequence, small clefts are formed in the cardiac muscle leading to blood leakage into the pericardial cavity and an arrest of heart function. The defects in the BM separating the brain from the adjacent mesenchyme caused invasion of brain tissue into the overlaying ectoderm leading to abnormal expansion of neuroepithelium, neuronal ectopias, and exencephaly. Finally, homozygotes developed a severe defect in cartilage, a tissue that lacks BMs. The chondrodysplasia is characterized by a reduction of the fibrillar collagen network, shortened collagen fibers, and elevated expression of cartilage extracellular matrix genes, suggesting that perlecan protects cartilage extracellular matrix from degradation.
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