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Review Cell Fusion and Some Subcellular Properties Of REVIEW CELL FUSION AND SOME SUBCELLULAR PROPERTIES OF HETEROKARYONS AND HYBRIDS SAIMON GORDON From the Genetics Laboratory, Department of Biochemistry, The University of Oxford, England, and The Rockefeller University, New York 10021 I. INTRODUCTION The technique of somatic cell fusion has made it first cell hybrids obtained by this method. The iso- possible to study cell biology in an unusual and lation of hybrid cells from such mixed cultures direct way. When cells are mixed in the presence of was greatly facilitated by the Szybalski et al. (6) Sendai virus, their membranes coalesce, the cyto- and Littlefield (7, 8) adaptation of a selective me- plasm becomes intermingled, and multinucleated dium containing hypoxanthine, aminopterin, and homo- and heterokaryons are formed by fusion of thymidine (HAT) to mammalian systems. similar or different cells, respectively (1, 2). By Further progress followed the use of Sendai fusing cells which contrast in some important virus by Harris and Watkins to increase the biologic property, it becomes possible to ask ques- frequency of heterokaryon formation (9). These tions about dominance of control processes, nu- authors exploited the observation by Okada that cleocytoplasmic interactions, and complementa- UV irradiation could be used to inactivate Sendai tion in somatic cell heterokaryons. The multinucle- virus without loss of fusion efficiency (10). It was ate cell may divide and give rise to mononuclear therefore possible to eliminate the problem of virus cells containing chromosomes from both parental replication in fused cells. Since many cells carry cells and become established as a hybrid cell line receptors for Sendai virus, including those of able to propagate indefinitely in vitro. The chro- different species, it became possible to fuse a va- mosome constitution of the hybrid cells can then riety of cell types, including differentiated and remain relatively stable, as in intraspecific crosses, nondividing cells. or may be unstable, as in man-rode~nt interspecific The technique of cell fusion has already been hybrids which tend to lose human chromosomes applied to the study of many problems in the selectively, as first noted by Weiss and Green (3). genetics and cellular biology of somatic cells. The This combination of cell mating and chromosome purpose of this paper is to provide a selective segregation makes it possible to perform genetic review of experimental studies that are of special analysis on somatic cells, to assign human gene interest to the cell biologist, with emphasis on the products to individual chromosomes, and to study principles and pitfalls underlying the use of this the control of gene expression in animal cells. technique. Topics which have been extensively Originally, cell hybridization was an uncon- reviewed elsewhere will not be discussed in detail trolled, apparently spontaneous event which oc- (11-14). These include linkage analysis and chro- curred rarely when different cells were simply mosome assignment (15), virus rescue by cell mixed and co-cultivated. Barski et al. (4), and hybridization (12), and the application of cell Ephrussi and Weiss (5) isolated and studied the hybridization to the study of malignancy (16). THE JOURNAL OF CELL BIOLOGY VOLUME 67, 1975 pages 257-280 257 II. METHODS varies a great deal, presumably depending on the presence of virus receptors and on the chemical The genetic analysis of somatic cells by hy- composition of the plasma membrane of the cell bridization depends on the availability of effi- (17). Other viruses that promote cell fusion, such cient methods to fuse cells and purify hybrids. as Newcastle disease virus, have been little used In this section, we deal with the use of viral and for the purpose of cell hybridization. other agents to increase the frequency of hetero- A chemical fusion procedure would be de- karyon formation, and we review our under- sirable, to avoid using a virus as a reagent and standing of the mechanism of fusion. We also to fuse cells refractory to virus (24). Lysolecithin examine the use of mutant cells in devising and other lipids have had limited use hitherto, suitable hybrid selection systems and consider partly because they often cause extensive cell the application of new methods of cell enuclea- lysis (25). Fusion by microsurgery perhaps offers tion to fusion of subcellular fractions. more promise as an alternative (26, 27). Pre- A. Cell Fusion selected cells, synchronized in telophase, can be aligned and induced to fuse by micromanipula- Sendai virus is the agent used most frequently tion. The bicellular hybrids can then be isolated to promote cell fusion. Like other paramyxo- without the use of selection media. Although viruses it consists of a ribonucleoprotein core this method may be more cumbersome than and a lipoprotein envelope (17). Virus particles mass fusion, it offers a unique opportunity for mature by budding from the cell surface, and the control and direct observation of early clone evo- envelope contains virus-determined proteins and lution. It should also facilitate the fusion of cells lipids incorporated from the host cell. Several which differ in ploidy, so that the influence of biological properties of paramyxoviruses have dosage on subsequent gene expression could be recently been associated with particular envelope studied to advantage. Microsurgical enucleation proteins (18-20). Viral hemagglutinin and and fusion may cause less cell damage than neuraminidase activity are found in a spike glyco- cytochalasin B and Sendai virus in particularly protein (HN) of mol wt 69,000. Cell-fusing ac- delicate renucleation experiments (28, 29). tivity seems to be associated with the presence of Finally, freshly prepared plant protoplasts can a 53,000 mol wt glycoprotein (F) which can be be induced to fuse by intimate cell contact (30, generated from a larger precursor molecule (Fo) 31), and powerful "fusogens" of protoplasts such by limited proteolytic cleavage in vivo or in vitro. as polyethylene glycol may also be effective in Sendai virus grown in different host cells can hybridization of mammalian cells. 1 differ in the content of this glycoprotein, which THE MECHANISM OF FUSION may also play a role in virus-induced hemolysis and the initiation of infection. However, the INTRODUCTION: Since membrane fusion plays ability to fuse cells may also depend on the an important role in many cellular functions in- presence of other components of the viral en- cluding endocytosis and secretion, cell fusion velope (21 ). could provide a useful model system for studying For the purpose of cell fusion, UV light (22) the biochemical and ultrastructural aspects of or B-propriolactone (23) is used to inactivate the the fusion process. In addition to viruses and virus, most of which is subsequently degraded lipids, a variety of other methods including high within phagocytic vacuoles of the cell. When temperature (32), Ca ++ at pH 10.5 (33), or used in moderate concentrations, the virus has phospholipase C (34) can initiate fusion. These no obvious deleterious effect on the fused cell. systems offer the advantage of synchronized, mas- A relatively high concentration of inactivated sive fusion which can be readily monitored by virus fuses cells "from without" by direct inter- phase-contrast microscopy. Mammalian erythro- action with the plasma membrane, but cells can cytes (35), nucleated avian erythrocytes, and also be fused "from within" after replication ~a various other cell types have been used for these the cell. A measure of control of fusion effi- studies. ciency is possible by promoting cell contact, VIRUS-INDUCED FUSION= The possible role of either in suspension or on a surface, and by t Pontecorvo, G. Production of indefinitely multiplying varying the proportion of each cell type used. mammalian somatic cell hybrids by polyethylene glycol The susceptibility of different cells to fusion (PEG) treatment. Manuscript submitted for publication. THE JOURNAL OF CELL BIOLOGY VOLUME 67, 1975 specific viral components in cell fusion has al- directly on the plasma membrane or by an in- ready been mentioned. Viral hemagglutinin and direct mechanism. neuraminidase may contribute an ancillary func- Morphologic studies hitherto have not resolved tion in promoting cell contact and modification of conflicting hypotheses whether fusion occurs the plasma membrane. The virus binds to sialyl- directly between cells or via an intermediate glycoprotein receptors on the cell surface and can step of fusion with the viral envelope (46-48). elute from the cell by hydrolysis of terminal Recent studies with newer methods are beginning neuraminic acid residues (36). Studies with to shed more light on the initial stages of virus- iiposomes suggest that gangliosides also serve cell interaction. After brief periods of incubation as binding sites (37), in line with earlier observa- of virus with nonendocytic cells such as erythro- tions that a high ganglioside to phosphatidyl cytes, the pattern of distribution of viral compo- ethanolamine ratio of cellular lipids is asso- nents suggests that the viral envelope is able to ciated with enhanced fusibility (17). Cell recep- fuse directly with the plasma membrane (49). tors for paramyxoviruses may differ with cell Studies with ferritin-labeled antibodies show that type, e.g., T vs. B lymphocytes (38), and can viral antigens do not remain as clusters, but even be absent, as in horse erythrocytes (39). probably become dispersed within the plane of the Virus can be bound to such cells by concanavalin membrane. The use of combined freeze-fracture A and will induce hemolysis, but cell fusion and immunologic labeling techniques (50) in- has not yet been demonstrated in this instance. dicates that intramembranous particles, which Several stages can be distinguished in the may contain the glycoprotein receptors for virus fusion process (40). The first step of viral binding (51), become aggregated during the early stages to the cell surface is independent of ions and of fusion. It is not yet clear how specific these occurs readily in the cold.
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