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Perlecan maintains the integrity of cartilage and some basement membranes.

Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fässler R - J. Cell Biol. (1999)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, Lund University, S-221 85 Lund, Sweden.

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 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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Exencephaly and neuronal ectopias develop in the anterior region of the forebrain. (A and B) Hematoxylin/eosin staining of sagittal brain sections from wild-type (A) and perlecan- (B) E11.5 embryos. Note the extension and the thinning of the anterior part of the forebrain in the perlecan- embryo (upper box in B). Ectopias are visible ventral of the medial ganglionic eminence (arrow) in the homozygous embryo. (C–F) Higher magnification of the lower boxes indicated in A and B. In a normal brain, the neuroepithelium and the underlying mesenchyme are separated by a BM (C) that contains laminin-1 (E). In the perlecan- brain, the BM is discontinuous (D, arrow) and shows interrupted laminin-1 staining (F, arrow). (G and H) Higher magnification of the upper boxes indicated in A and B. In a normal brain, the neuroepithelium and the overlying mesenchyme are separated by a BM (G). In the perlecan- brain, neuroepithelial cells have invaded the overlying ectoderm (H, arrow). (I–L) Immunohistochemical localization of nestin and β-tubulin type III in the neocortex of normal and perlecan- embryos. The neocortex of the wild-type embryo contains nestin-positive cells (I) and a few β-tubulin type III–positive cells in the cortical subplate (K). Ectopic cells in the perlecan- embryo are positive for nestin (J) but negative for β-tubulin type III (L). (M) Hematoxylin/eosin staining of the forebrain region of an E11.5 homozygote showing a defect in the ectoderm and a small hole of 5–10 μm (arrow). Note that the amniotic membrane is still intact (arrowhead). (N–Q) Nissl staining of coronal sections of wild-type (N and P) and perlecan- (O and Q) E17.5 forebrain regions. The perlecan- brain shows a ruffled surface, large ectopias, and abnormal lamination (O). Posterior to this area, the ruffles and defects in lamination are less severe (Q). Abbreviations: mz, marginal zone; cp, cortical plate; iz, intermediate zone; and vz, ventricular zone. Bars: (C–L) 125 μm; (M) 250 μm; and (N–Q) 500 μm.
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Figure 4: Exencephaly and neuronal ectopias develop in the anterior region of the forebrain. (A and B) Hematoxylin/eosin staining of sagittal brain sections from wild-type (A) and perlecan- (B) E11.5 embryos. Note the extension and the thinning of the anterior part of the forebrain in the perlecan- embryo (upper box in B). Ectopias are visible ventral of the medial ganglionic eminence (arrow) in the homozygous embryo. (C–F) Higher magnification of the lower boxes indicated in A and B. In a normal brain, the neuroepithelium and the underlying mesenchyme are separated by a BM (C) that contains laminin-1 (E). In the perlecan- brain, the BM is discontinuous (D, arrow) and shows interrupted laminin-1 staining (F, arrow). (G and H) Higher magnification of the upper boxes indicated in A and B. In a normal brain, the neuroepithelium and the overlying mesenchyme are separated by a BM (G). In the perlecan- brain, neuroepithelial cells have invaded the overlying ectoderm (H, arrow). (I–L) Immunohistochemical localization of nestin and β-tubulin type III in the neocortex of normal and perlecan- embryos. The neocortex of the wild-type embryo contains nestin-positive cells (I) and a few β-tubulin type III–positive cells in the cortical subplate (K). Ectopic cells in the perlecan- embryo are positive for nestin (J) but negative for β-tubulin type III (L). (M) Hematoxylin/eosin staining of the forebrain region of an E11.5 homozygote showing a defect in the ectoderm and a small hole of 5–10 μm (arrow). Note that the amniotic membrane is still intact (arrowhead). (N–Q) Nissl staining of coronal sections of wild-type (N and P) and perlecan- (O and Q) E17.5 forebrain regions. The perlecan- brain shows a ruffled surface, large ectopias, and abnormal lamination (O). Posterior to this area, the ruffles and defects in lamination are less severe (Q). Abbreviations: mz, marginal zone; cp, cortical plate; iz, intermediate zone; and vz, ventricular zone. Bars: (C–L) 125 μm; (M) 250 μm; and (N–Q) 500 μm.

Mentions: Histological analysis of brain sections from normal and perlecan- E9.5 embryos revealed normal BM between neural tissue and mesenchyme (not shown). At E11.5, 70% of homozygotes showed areas in which the BM surrounding the telencephalic vesicles was disrupted (Fig. 4D and Fig. F), and the brain tissue had invaded into the cephalic mesenchyme and fused with the overlaying ectoderm (Fig. 4 H). Immunostaining revealed that the ectopias contained many nestin-positive cells (a marker for neuroepithelial cells; Fig. 4I and Fig. J), but lacked βIII isotype tubulin-positive cells (a marker for committed neurons; Fig. 4K and Fig. L). In the ectopic region, the neuroepithelium appeared thickened and the cells in the ventricular zone region were round instead of elongated as observed in the neocortex of normal embryos (Fig. 4G and Fig. H). At E11.5, clusters of neuroepithelial cells were exposed to the amniotic cavity and formed small disruptions of 5–10 μm (Fig. 4 M). Immunostaining for proliferative cells with Ki-67 antibodies and for apoptotic cells with TUNEL labeling revealed no abnormalities in E10.5 and E11.5 perlecan- brain tissues, neither in ectopias nor in normal appearing areas of the neocortex (not shown). At later stages, several homozygotes without obvious exencephaly showed a ruffled brain surface because the marginal zone of the neocortex was studded with large ectopias associated with a severe distortion of the laminar architecture of the cortex (Fig. 4O and Fig. Q).


Perlecan maintains the integrity of cartilage and some basement membranes.

Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fässler R - J. Cell Biol. (1999)

Exencephaly and neuronal ectopias develop in the anterior region of the forebrain. (A and B) Hematoxylin/eosin staining of sagittal brain sections from wild-type (A) and perlecan- (B) E11.5 embryos. Note the extension and the thinning of the anterior part of the forebrain in the perlecan- embryo (upper box in B). Ectopias are visible ventral of the medial ganglionic eminence (arrow) in the homozygous embryo. (C–F) Higher magnification of the lower boxes indicated in A and B. In a normal brain, the neuroepithelium and the underlying mesenchyme are separated by a BM (C) that contains laminin-1 (E). In the perlecan- brain, the BM is discontinuous (D, arrow) and shows interrupted laminin-1 staining (F, arrow). (G and H) Higher magnification of the upper boxes indicated in A and B. In a normal brain, the neuroepithelium and the overlying mesenchyme are separated by a BM (G). In the perlecan- brain, neuroepithelial cells have invaded the overlying ectoderm (H, arrow). (I–L) Immunohistochemical localization of nestin and β-tubulin type III in the neocortex of normal and perlecan- embryos. The neocortex of the wild-type embryo contains nestin-positive cells (I) and a few β-tubulin type III–positive cells in the cortical subplate (K). Ectopic cells in the perlecan- embryo are positive for nestin (J) but negative for β-tubulin type III (L). (M) Hematoxylin/eosin staining of the forebrain region of an E11.5 homozygote showing a defect in the ectoderm and a small hole of 5–10 μm (arrow). Note that the amniotic membrane is still intact (arrowhead). (N–Q) Nissl staining of coronal sections of wild-type (N and P) and perlecan- (O and Q) E17.5 forebrain regions. The perlecan- brain shows a ruffled surface, large ectopias, and abnormal lamination (O). Posterior to this area, the ruffles and defects in lamination are less severe (Q). Abbreviations: mz, marginal zone; cp, cortical plate; iz, intermediate zone; and vz, ventricular zone. Bars: (C–L) 125 μm; (M) 250 μm; and (N–Q) 500 μm.
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Figure 4: Exencephaly and neuronal ectopias develop in the anterior region of the forebrain. (A and B) Hematoxylin/eosin staining of sagittal brain sections from wild-type (A) and perlecan- (B) E11.5 embryos. Note the extension and the thinning of the anterior part of the forebrain in the perlecan- embryo (upper box in B). Ectopias are visible ventral of the medial ganglionic eminence (arrow) in the homozygous embryo. (C–F) Higher magnification of the lower boxes indicated in A and B. In a normal brain, the neuroepithelium and the underlying mesenchyme are separated by a BM (C) that contains laminin-1 (E). In the perlecan- brain, the BM is discontinuous (D, arrow) and shows interrupted laminin-1 staining (F, arrow). (G and H) Higher magnification of the upper boxes indicated in A and B. In a normal brain, the neuroepithelium and the overlying mesenchyme are separated by a BM (G). In the perlecan- brain, neuroepithelial cells have invaded the overlying ectoderm (H, arrow). (I–L) Immunohistochemical localization of nestin and β-tubulin type III in the neocortex of normal and perlecan- embryos. The neocortex of the wild-type embryo contains nestin-positive cells (I) and a few β-tubulin type III–positive cells in the cortical subplate (K). Ectopic cells in the perlecan- embryo are positive for nestin (J) but negative for β-tubulin type III (L). (M) Hematoxylin/eosin staining of the forebrain region of an E11.5 homozygote showing a defect in the ectoderm and a small hole of 5–10 μm (arrow). Note that the amniotic membrane is still intact (arrowhead). (N–Q) Nissl staining of coronal sections of wild-type (N and P) and perlecan- (O and Q) E17.5 forebrain regions. The perlecan- brain shows a ruffled surface, large ectopias, and abnormal lamination (O). Posterior to this area, the ruffles and defects in lamination are less severe (Q). Abbreviations: mz, marginal zone; cp, cortical plate; iz, intermediate zone; and vz, ventricular zone. Bars: (C–L) 125 μm; (M) 250 μm; and (N–Q) 500 μm.
Mentions: Histological analysis of brain sections from normal and perlecan- E9.5 embryos revealed normal BM between neural tissue and mesenchyme (not shown). At E11.5, 70% of homozygotes showed areas in which the BM surrounding the telencephalic vesicles was disrupted (Fig. 4D and Fig. F), and the brain tissue had invaded into the cephalic mesenchyme and fused with the overlaying ectoderm (Fig. 4 H). Immunostaining revealed that the ectopias contained many nestin-positive cells (a marker for neuroepithelial cells; Fig. 4I and Fig. J), but lacked βIII isotype tubulin-positive cells (a marker for committed neurons; Fig. 4K and Fig. L). In the ectopic region, the neuroepithelium appeared thickened and the cells in the ventricular zone region were round instead of elongated as observed in the neocortex of normal embryos (Fig. 4G and Fig. H). At E11.5, clusters of neuroepithelial cells were exposed to the amniotic cavity and formed small disruptions of 5–10 μm (Fig. 4 M). Immunostaining for proliferative cells with Ki-67 antibodies and for apoptotic cells with TUNEL labeling revealed no abnormalities in E10.5 and E11.5 perlecan- brain tissues, neither in ectopias nor in normal appearing areas of the neocortex (not shown). At later stages, several homozygotes without obvious exencephaly showed a ruffled brain surface because the marginal zone of the neocortex was studded with large ectopias associated with a severe distortion of the laminar architecture of the cortex (Fig. 4O and Fig. Q).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Pathology, Lund University, S-221 85 Lund, Sweden.

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 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.

Show MeSH
Related in: MedlinePlus