The molecules of the collapsin/semaphorin gene family have been thought to play an essential role in axon guidance during development. Semaphorin III/D is a member of this family, has been shown to repel dorsal root ganglion (DRG) axons in vitro, and has been implicated in the patterning of sensory afferents in the spinal cord. Although semaphorin III/D mRNA is expressed in a wide variety of neural and nonneural tissues in vivo, the role played by semaphorin III/D in regions other than the spinal cord is not known. Here, we show that mice homozygous for a targeted mutation in semaphorin III/D show severe abnormality in peripheral nerve projection. This abnormality is seen in the trigeminal, facial, vagus, accessory, and glossopharyngeal nerves but not in the oculomotor nerve. These results suggest that semaphorin III/D functions as a selective repellent in vivo.
Abstract. A major collagen-binding heat shock protein of molecular mass 47,000 D was found to bind to collagen by a pH-dependent interaction; binding was abolished at pH 6.3. Native 47-kD protein could therefore be purified from chick embryo homogenates in milligram quantities by gelatin-affinity chromatography and gentle acidic elution. Rat monoclonal and rabbit polyclonal antibodies were generated against the purified 47-kD protein. Immunofluorescence microscopy of cultured chick embryo fibroblasts with these antibodies revealed bright, granular perinuclear staining as well as a weaker reticular network structure towards the cell periphery, suggesting that this protein was located in the endoplasmic reticulum. No immunofluorescence staining was detected on the cell surface. Doublestaining experiments with these antibodies and fluorescently labeled wheat-germ agglutinin suggested that the 47-kD protein was absent from the Golgi apparatus. Localization of the 47-kD protein in the endoplasmic reticulum but not in the Golgi complex was confirmed by immunoelectron microscopy. In vivo localization studies using immunohistochemistry of cryostat sections of chick liver revealed that the 47-kD protein was present in fibrocytes, Kupffer cells, and smooth muscle cells. It was absent from hepatocytes and the epithelia of bile ducts or sinusoidal endothelium. This major transformation-and heat shockregulated glycoprotein is thus localized intracellularly, is expressed in only certain cells, and functions in a pH-regulated manner. These findings suggest that this glycoprotein is not likely to be a general cell-surface collagen receptor, but may instead play roles in intracellular protein processing or translocation.ECENT studies have characterized a major collagenbinding protein of Mr 47,000 D that is present in a wide variety of cultured cell types (12,15,16,21). This membrane-associated glycoprotein binds to gelatin (denatured collagen types I and ~ and to native collagen types I, M, and IV (12,15,16,21). It represents the major protein besides fibronectin that binds to collagen-affinity columns under physiological salt conditions, and it can be the major concanavalin A-binding protein of membrane preparations (6,12,15,16,21).Previously, we reported (16) that this 47-kD collagen/ gelatin-binding protein corresponds to a previously described membrane protein (6,19), and that its synthesis and phosphorylation are regulated in opposing directions by an oncogene product. In addition, we found that this protein is a novel heat-shock protein (15). Studies of its specificity of binding indicated that it is relatively specific for the collagens, although it can bind to fetuin (16; Nagata, K., S. Saga, and K. M. Yamada, unpublished); whether such interactions with noncollagenous proteins provide a mechanism for reguDr. Saga's present address is The Second Department of Pathology, Nagoya University School of Medicine, Nagoya 466, Japan. Dr. Nagata's present address is Chest Disease Research Institute, Kyoto University, Kyoto 606, J...
Abstract. Heat shock proteins of chick embryo fibroblasts were analyzed on SDS polyacrylamide gradient gets and were found to include not only three previously well-characterized proteins of 25,000, 73,000, and 89,000 D, but also a 47,000-D protein. Twodimensional gel electrophoresis revealed that this protein was unusually basic (pI = 9.0) and corresponded to a recently characterized, major gelatin-and collagen-binding protein. The induction of synthesis of this 47,000-D membrane glycoprotein after heat stress of fibroblasts was particularly apparent in preparations isolated by gelatin-affinity chromatography.Regulation of this 47,000-D phosphoprotein was more sensitive than that of three major heat shock proteins in that a substantial stimulation of synthesis occurred at even 42°C, as well as at higher temperature. Phosphorylation of the 47,000-D protein was not altered after heat shock. These studies establish this phosphorylated membrane glycoprotein as a member of the heat shock/stress protein family, and they add collagen binding to the unexpectedly diverse spectrum of biochemical activities induced by exposure of cells to stress.
This study was designed to investigate possible involvement of type IV collagenolytic matrix metalloproteinases (MMPs; 72-kDa type IV collagenase [MMP-2], 92-kDa type IV collagenase [MMP-9]), and the respective specific tissue inhibitors of these MMPs (TIMP-2 and TIMP-1) in the development of adult respiratory distress syndrome (ARDS). We determined the concentrations of these enzymes in the bronchoalveolar lavage fluid (BALF) from patients with ARDS using newly developed sensitive one-step sandwich enzyme immunoassay methods. BALF obtained from the 17 patients and eight healthy volunteer control subjects were also used for the analysis of the number of the cellular component. Concentrations of the 7S portion of type IV collagen and laminin in the BALF were measured as markers of basement membrane disruption. In the BALF from the ARDS patients, the concentrations of MMP-2 (66.7 +/- 57.0 ng/ml versus < 7.0 ng/ml for controls, p < 0.01) and MMP-9 (118.0 +/- 309.3 ng/ml versus 9.0 +/- 9.5 ng/ml for controls, p < 0.05), and the specific inhibitor of MMP-9 (TIMP-1) (161.0 +/- 145.0 ng/ml versus < 50 ng/ml for controls, p < 0.01) were significantly higher compared with those for healthy control subjects. In the ARDS patients, the concentrations of MMP-2 correlated both with those of 7S collagen and laminin; MMP-9 with the concentration of 7S collagen and the number of neutrophils. These findings suggest that the increased concentration of collagenolytic MMPs in lung plays a role in the pathogenesis of ARDS.
In order to find a relationship between ductal hyperplasia and carcinoma of the pancreas, histological and histochemical examinations were made on pancreatic specimens of 1,174 autopsy patients with special attention to the age incidence of the former. Ductal hyperplasia was divided into 3 types; nonpapillary, papillary, and atypical hyperplasia. All three types of hyperplasia and ductal carcinoma showed a similar tinctorial property in mucous histochemistry. In general, atypical hyperplasia was seen in the pancreas having papillary hyperplasia which was found in the pancreas associated with nonpapillary hyperplasia. All three types of hyperplasia were apparently more frequent in cancerous pancreases than in non-cancerous ones. They were also more common in the head of the pancreas than in the body and tail. Age incidence also suggests a sequential change from nonpapillary hyperplasia through papillary and atypical ones to carcinoma.Cancer 43:1418-1428, 1979.HE GREAT MAJORITY of carcinomas of the T exocrine elements of the pancreas is of duct cell rigi in.^,^ The relationship of pancreatic duct hyperplasia to pancreatic carcinoma has been emphasized by Sommers et al.," because of the high incidence of ductal hyperplasia in carcinomatous pancreases. Cubilla and Fitzgerald3 also found a similar relation. However, following Birnstingl's report, they noted that there was obstruction to the pancreatic duct in most of their cases, a complicating factor in the assessment of ductal papillary hyperplasia. Birnstingl,2 in cases with a variety of acute and chronic nonpancreatic diseases and. no cancer of the pancreas, reported an incidence of 29% having hyperplastic columnar epithelium. It seems to be necessary for clarification of the relationship between ductal hyperplasia and carcinoma of the pancreas to reevaluate the age incidence of ductal hyperplasia in noncancerous pancreases. If ductal hyperplasia is a change preceding pancreatic carcinoma, it should appear in younger patients than those with pancreatic carcinoma. The aim of the present study is to find possible From the 2nd Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan.Address for reprints: S. Komka, MD, T h e 2nd Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan.Accepted for publication May 22, 1978. transition from ductal hyperplasia to carcinoma by histology and mucous histochemistry and to study age difference in incidence between ductal hyperplasia and pancreatic carcinoma. MATERIALS AND METHODSUsing autopsy cases at our laboratory, available routine microscopic sections of 1,174 pancreases of which 24 had infiltrating carcinoma were examined. Mostly one section, sometimes two or more sections, was prepared from one pancreas. Selected cases were stained with periodic acid Schiff/alcian blue pH 2.5 and high iron diamine/alcian blue pH 2.5.'*"Ductal hyperplasia was defined as ducts with large epithelial cells which are more than twice as tall as normal cells, because en...
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