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Correspondence to: H. Dariush Fahimi, Inst. for Anatomy and Cell Biology, Div. of Medical Cell Biology, U. of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
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Summary |
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The past decade has witnessed unprecedented progress in elucidation of the complex problems of the biogenesis of peroxisomes and related human disorders, with further deepening of our understanding of the metabolic role of this ubiquitous cell organelle. There have been many recent reviews on biochemical and molecular biological aspects of peroxisomes, with the morphology and cytochemistry receiving little attention. This review focuses on the state-of-the-art cytochemical techniques available for investigation of peroxisomes. After a brief introduction into the use of the 3,3'-diaminobenzidine method for localization of catalase, which is still most commonly used for identification of peroxisomes, the cerium technique for detection of peroxisomal oxidases is discussed. The influence of the buffer used in the incubation medium on the ultrastructural pattern obtained in rat liver peroxisomes in conjunction with the localization of urate oxidase in their crystalline cores is discussed, particularly since Tris-maleate buffer inhibits the enzyme activity. In immunocytochemistry, quantitation of immunogold labeling by automatic image analysis enables quantitative assessment of alterations of proteins in the matrix of peroxisomes. This provides a highly sensitive approach for analysis of peroxisomal responses to metabolic alterations or to xenobiotics. The recent evidence suggesting the involvement of ER in the biogenesis of "preperoxisomes" is mentioned and the potential role of preembedding immunocytochemistry for identification of ER-derived early peroxisomes is emphasized. The use of GFP expressed with a peroxisomal targeting signal for the investigation of peroxisomes in living cells is briefly discussed. Finally, the application of in situ hybridization for detection of peroxisomal mRNAs is reviewed, with emphasis on a recent protocol using perfusion-fixation, paraffin embedding, and digoxigenin-labeled cRNA probes, which provides a highly sensitive method for detection of both high- and low-abundance mRNAs encoding peroxisomal proteins. (J Histochem Cytochem 47:12191232, 1999)
Key Words: DAB, cerium, immunoelectron microscopy, GFP, Zellweger syndrome, in situ hybridization, oxidase, catalase, PEX5 -/-, knockout mouse
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Introduction |
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Cytochemical techniques, including electron microscopy and morphometry, have contributed significantly to our present knowledge of peroxisomes. They were discovered first by electron microscopy and called microbodies (
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Because the DAB technique for localization of catalase, a marker enzyme of peroxisomes, is still the most commonly used cytochemical method for their investigation and one that is often used in an initial morphological survey for detection and identification of this organelle, it is treated first.
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The DAB Technique for Localization of Peroxisomal Catalase |
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The peroxidase substrate 3,3'-diaminobenzidine was originally introduced by
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DAB-stained semithin sections have been used for morphometric assessment of the peroxisomal compartment and its alterations in response to xenobiotics (
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Cerium Technique for Detection of Oxidase Activity in Peroxisomes |
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The cerium technique is presently the method of choice for light and electron microscopic detection of peroxisomal oxidases, although alternative methods based on reduction of ferricyanide and tetrazolium salts were used in earlier years (for a review of the early literature on peroxisomal oxidases see
The final reaction product of cerium chloride with H2O2 is cerium perhydroxide, which is electron-dense (
An important contribution of cytochemistry of oxidases to the biology of peroxisomes has been the discovery of their heterogeneity both in the liver lobule and even within the same cell in rat liver and kidney (
Cytochemistry with cerium, together with immunoelectron microscopy, has revealed that some oxidases form distinct subcompartments in the matrix of peroxisomes. Therefore, in addition to the electron-dense polytubular cores of UOX, D-amino acid oxidase forms a focal noncrystalline condensation in the central part of the matrix and -hydroxyacid oxidase-B forms the so-called marginal plates (Figure 1g and Figure 1h). The latter are usually flat plate-like structures associated closely with the inner aspect of the peroxisome membrane (
-hydroxy acid oxidase-B (K. Zaar, unpublished observations). In preparations incubated with cerium for detection of D-amino acid oxidase, the marginal plates appear as a negative image beneath the peroxisomal membrane (Figure 1g). A narrow gap of 710 nm separates the latter from the marginal plates, which may show even the cubical protomeres of
-hydroxy acid oxidase-B seen only after isolation and negative staining (
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Immunocytochemical Techniques |
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During the past two decades, immunolabeling techniques have gained a great deal in importance, becoming the principal tools for morphological investigation of peroxisomes. With the availability of antibodies against most peroxisomal proteins and development of suitable protocols for processing of cells and tissues, immunofluoresence and immunoelectron microscopy are now almost routine procedures in peroxisome research. Moreover, those techniques have become indispensible tools in diagnosis and research of peroxisomal diseases revealing, e.g., the presence of the so-called peroxisomal ghosts in the liver of patients with generalized peroxisome disorders (
Whereas in the first immunocytochemical studies ferritin- and peroxidase-labeled antibodies were used (
Immunogold labeling in combination with automatic image analysis permits quantitative assessment of alterations of proteins in peroxisomes in response to treatment of rodents and cell cultures with different agents ( (PPAR-
) which mediates the xenobiotic-induced response (
Recently, an isoform of lactate dehydrogenate (LDH) was detected in rat hepatic peroxisomes by cell fractionation and immunocytochemistry (
The application of immunoelectron microscopy to isolated subcellular fractions has led to the disovery of peroxisomes with lower buoyant density than the regular particles. Whereas the regular peroxisomes in rat liver band at a density of 1.231.24 g/cm2, in regenerating rat liver particles with lower density (1.20 g/cm2 and lower) were found which in pulse-labeling studies exhibited a higher initial rate of incorporation of radioactivity, suggesting that they could be precursor particles to regular peroxisomes ( is probably involved in this process (
Although the concept of derivation of peroxisomes from the endoplasmic reticulum, originally advanced by Alex Novikoff (for a review see
The application of immunofluorescence has revealed the existence of tubular peroxisomes measuring up to several microns, next to small spherical particles in HepG2 cells (Figure 4a and Figure 4b) (
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In contrast to tubular mitochondria (
As mentioned, expression of the GFP with the peroxisomal targeting signal 1 (SKL) has been used successfully for in vivo labeling of peroxisomes in yeast and mammalian cells (
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In Situ Hybridization (ISH) |
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The main application of ISH in peroxisome research has been for chromosomal localization of genes encoding peroxisomal proteins and for assessment of the cellular and tissue-specific distribution of their corresponding mRNAs. According to the published reports on chromosomal assignment studies in mammals the "peroxisomal genes" are not clustered on specific chromosomes but rather are found on different ones.
There have been only a few studies on application of ISH for the assessment of tissue-specific and cellular distribution of "peroxisomal mRNAs" (for a recent review see
The main features of the protocol used by (
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Acknowledgments |
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Supported by SFB-352 (project C7), SFB 601 (project B1), and grants FA 146/3-1, Ba1155/1-3, all from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, and by a grant from the European Community DGXII-PL96-3569.
We thank all our colleagues and collaborators at the Institute for Anatomy and Cell Biology at the University of Heidelberg for their many helpful suggestions and discussions. In particular, Drs Alfred Völkl, Sabine Angermüller, Kurt Zaar, and Konstantin Beier have contributed over the years to many of the important results from our laboratory summarized here. We also thank Gabrielle Burger (Leica; Heidelberg, Germany) for assistance with preparation of CLSM and two photon microscopic images (Figure 4a and Figure 4b) and Dr Kurt Zaar for the micrograph on immunocytochemical localization of -hydroxy acid oxidase B (marginal plates; Figure 1h). The technical assistance of Gabi Krämer and Heike Steininger is gratefully acknowledged.
Received for publication April 29, 1999; accepted May 18, 1999.
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