The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?

The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?

Gangliosides are characteristic extracellular-facing plasma membrane determinants in vertebrate brain. The four major gangliosides (GM1, GD1a, GD1b and GT1b) dominate among more than one hundred glycolipid structures in nervous tissue. During brain development the expression of simple gangliosides s...

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Дата:2010
Автори: Heffer-Lauc, M., Mojsovic-Cuic, A., Hrabac, P., Viljetic, B., Dikic, D.
Формат: Стаття
Мова:English
Опубліковано: Інститут молекулярної біології і генетики НАН України 2010
Назва видання:Вiopolymers and Cell
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Reviews
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Цитувати:The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance? / M. Heffer-Lauc, A. Mojsovic-Cuic, P. Hrabac, B. Viljetic, D. Dikic // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 105-114. — Бібліогр.: 88 назв. — англ.

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spelling irk-123456789-1538742019-07-06T20:25:29Z The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance? Heffer-Lauc, M. Mojsovic-Cuic, A. Hrabac, P. Viljetic, B. Dikic, D. Reviews Gangliosides are characteristic extracellular-facing plasma membrane determinants in vertebrate brain. The four major gangliosides (GM1, GD1a, GD1b and GT1b) dominate among more than one hundred glycolipid structures in nervous tissue. During brain development the expression of simple gangliosides shifts toward more complex ones, accompanied by a multiple increase in their total amount. The shift is precisely regulated and some specific structures represent well established neurodevelopmental milestones. From the evolutionary perspective, the ganglioside content in fish and amphibian brain is significantly lower than in mammalian brain, but the general variability is greater. More-polar structures, abundant in Antarctic fishes, are rare in higher vertebrates or expressed only in a narrow developmental frame. Reptiles, birds and mammals share identical common structures expressed in similar patterns with minor interspecies differences. On the contrary, fish and amphibian brains show significant interspecies differences in amount, structure and expression patterns. The initial assumption of evolutionary studies was that the variations in lipid content, particularly the glycolipid content, during temperature adaptations in ectothermic and hibernating heterothermic animals, represent an efficient molecular mechanism of the membrane function preservation. Studies of ordered lipid domains in the last decade verified the ganglioside-mediated regulation of membrane proteins (receptor kinases, neurotransmitter receptors and ion channels) as well as receptor-ligand interaction important for cell signaling. Гангліозиди – характеристичні детермінанти, які локалізовані на зовнішній поверхні мембран клітин мозку хребетних. Чотири основних гангліозиди (GM1, GD1a, GD1b i GT1b) переважають серед сотень інших сполук гліколіпідів нервової тканини. У процесі розвитку мозку експресія простих гангліозидів зміщується у бік синтезу більш складних сполук, що супроводжується багаторазовим зростанням їхньої загальної кількості. Зміщення експресії – строго регульований процес, за якого поява деяких специфічних структур репрезентує добре відомі стадії розвитку нервової тканини. З точки зору еволюції вміст гангліозидів у мозку риб та амфібій значно нижчий, ніж у мозку ссавців, проте загальна їхня варіабельність суттєво вища. Більш полярні сполуки, які широко представлені у антарктичних риб, є рідкісними для ссавців або характерними для певного короткотривалого етапу онтогенезу. Плазуни, птахи і ссавці зберігають ідентичні спільні структури, що мають подібні патерни експресії з незначними міжвидовими відмінностями. Навпаки, для мозку риб та амфібій відзначено істотну міжвидову відмінність щодо кількості, структури та патерну експресії. Першочерговим припущенням еволюційного дослідження стало те, що варіації у вмісті ліпідів, зокрема гліколіпідів, під час температурної адаптації у холоднокровних і гетеротермних тварин, які впадають у сплячку, є високоефективним молекулярним механізмом захисту функціонування мембран. Вивчення впорядкованих доменів ліпідів за останнє десятиліття підтверджує гангліозид-опосередковану регуляцію мембранних білків (рецептори з кіназною активністю, рецептори нейротрансмітерів та іонні канали), так само як і взаємодію рецептор–ліганд, важливу для передачі позаклітинного сигналу. Ганглиозиды – характеристические детерминанты, локализованные на внешней поверхности мембран клеток мозга хребетных. Четыре основных ганглиозида (GM1, GD1a, GD1b и GT1b) преобладают среди сотень других соединений гликолипидов нервной ткани. В процессе развития мозга экспрессия простых ганглиозидов замещается синтезом более сложных соединений, что сопровождается многократным увеличением их общего количества. Смещение экспрессии – строго регулированный процесс, при котором появление некоторых специфических структур представляет хорошо известные стадии развития нервной ткани. Содержание ганглиозидов в мозге рыб и амфибий значительно ниже, чем в мозге млекопитающих, однако их общая вариабельность существенно выше. Более полярные соединения, широко представленные у антарктических рыб, являются редкими для млекопитающих или характерными для определенного кратковременного этапа онтогенеза. Пресмыкающиеся, птицы и млекопитающие сохраняют общие идентичные структуры с подобными паттернами экспрессии, имеющими незначительные межвидовые отличия. Наоборот, для мозга рыб и амфибий отмечены существенные межвидовые отличия, касающиеся количества, структуры и паттерна экспрессии. Первоочередным предположением эволюционного исследования стало то, что вариации в содержании липидов, в частности гликолипидов, во время температурной адаптации у хладнокровных и гетеротермных животных, впадающих в спячку, являются высокоэффективным молекулярным механизмом защиты функционирования мембран. Изучение упорядоченных доменов липидов за последнее десятилетие подтверждает ганглиозид-опосредованную регуляцию мембранных белков (рецепторы с киназной активностью, рецепторы нейротрансмиттеров и ионные каналы), так же как и взаимодействие рецептор–лиганд, важное для передачи внеклеточного сигнала. 2010 Article The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance? / M. Heffer-Lauc, A. Mojsovic-Cuic, P. Hrabac, B. Viljetic, D. Dikic // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 105-114. — Бібліогр.: 88 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00014C http://dspace.nbuv.gov.ua/handle/123456789/153874 577.114.5:57.017.2 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
language English
topic Reviews
Reviews
spellingShingle Reviews
Reviews
Heffer-Lauc, M.
Mojsovic-Cuic, A.
Hrabac, P.
Viljetic, B.
Dikic, D.
The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?
Вiopolymers and Cell
description Gangliosides are characteristic extracellular-facing plasma membrane determinants in vertebrate brain. The four major gangliosides (GM1, GD1a, GD1b and GT1b) dominate among more than one hundred glycolipid structures in nervous tissue. During brain development the expression of simple gangliosides shifts toward more complex ones, accompanied by a multiple increase in their total amount. The shift is precisely regulated and some specific structures represent well established neurodevelopmental milestones. From the evolutionary perspective, the ganglioside content in fish and amphibian brain is significantly lower than in mammalian brain, but the general variability is greater. More-polar structures, abundant in Antarctic fishes, are rare in higher vertebrates or expressed only in a narrow developmental frame. Reptiles, birds and mammals share identical common structures expressed in similar patterns with minor interspecies differences. On the contrary, fish and amphibian brains show significant interspecies differences in amount, structure and expression patterns. The initial assumption of evolutionary studies was that the variations in lipid content, particularly the glycolipid content, during temperature adaptations in ectothermic and hibernating heterothermic animals, represent an efficient molecular mechanism of the membrane function preservation. Studies of ordered lipid domains in the last decade verified the ganglioside-mediated regulation of membrane proteins (receptor kinases, neurotransmitter receptors and ion channels) as well as receptor-ligand interaction important for cell signaling.
format Article
author Heffer-Lauc, M.
Mojsovic-Cuic, A.
Hrabac, P.
Viljetic, B.
Dikic, D.
author_facet Heffer-Lauc, M.
Mojsovic-Cuic, A.
Hrabac, P.
Viljetic, B.
Dikic, D.
author_sort Heffer-Lauc, M.
title The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?
title_short The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?
title_full The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?
title_fullStr The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?
title_full_unstemmed The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?
title_sort quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance?
publisher Інститут молекулярної біології і генетики НАН України
publishDate 2010
topic_facet Reviews
url http://dspace.nbuv.gov.ua/handle/123456789/153874
citation_txt The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance? / M. Heffer-Lauc, A. Mojsovic-Cuic, P. Hrabac, B. Viljetic, D. Dikic // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 105-114. — Бібліогр.: 88 назв. — англ.
series Вiopolymers and Cell
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fulltext The quest for the ganglioside functions; what did we learn more from «evo-devo» or signaling of long-term maintenance? M. Heffer-Lauc, A. Mojsovic-Cuic1, P. Hrabac2, B. Viljetic, D. Dikic3 School of Medicine, Josip Juraj Strossmayer University of Osijek 4, Huttlerova, Osijek, Croatia, 31000 1University of Applied Health Studies, University of Zagreb 38, Mlinarska, Zagreb, Croatia, 10000 2Croatian Institute for Neuroscience, University of Zagreb 11, Salata, Zagreb, Croatia, 10000 3Faculty of Science, University of Zagreb 6, Rooseveltov trg, Zagreb, Croatia, 10000 mheffer@mefos.hr Gangliosides are characteristic extracellular-facing plasma membrane determinants in vertebrate brain. The four major gangliosides (GM1, GD1a, GD1b and GT1b) dominate among more than one hundred glycolipid structures in nervous tissue. During brain development the expression of simple gangliosides shifts toward more complex ones, accompanied by a multiple increase in their total amount. The shift is precisely regulated and some specific structures represent well established neurodevelopmental milestones. From the evolutionary perspective, the ganglioside content in fish and amphibian brain is significantly lower than in mammalian brain, but the general variability is greater. More-polar structures, abundant in Antarctic fishes, are rare in higher vertebrates or expressed only in a narrow developmental frame. Reptiles, birds and mammals share identical common structures expressed in similar patterns with minor interspecies differences. On the contrary, fish and amphibian brains show significant interspecies differences in amount, structure and expression patterns. The initial assumption of evolutionary studies was that the variations in lipid content, particularly the glycolipid content, during temperature adaptations in ectothermic and hibernating heterothermic animals, represent an efficient molecular mechanism of the membrane function preservation. Studies of ordered lipid domains in the last decade verified the ganglioside-mediated regulation of membrane proteins (receptor kinases, neurotransmitter receptors and ion channels) as well as receptor-ligand interaction important for cell signaling. Keywords: gangliosides, brain, evolution, development, cell-signaling, lipid rafts. Introduction Lipids constitute 50 % of brain dry we- ight [1]. Gangliosides contribute in the total lipid content with 10–12 % [2]. They are present in some intracellular structures, but prevail in external leaflet of plasma membrane, which gives them a role of the ma- jor cell surface determinants on vertebrate nerve cells [3]. Amphiphatic in nature, they consist of lipophilic ceramide moiety and hydrophilic sugar chain. Diffe- rently from other glycosphingolipids, the ganglioside sugar chain carries one or more sialic acid residues. At 105 ISSN 0233-7657. Biopolymers and Cell. 2010. Vol. 26. N 2 Ó Institute of Molecular Biology and Genetics NAS of Ukraine, 2010 the moment 188 ganglioside structures in vertebrate tissues have been described merely based on a variety of sugar chains, but heterogeneity is considerably wi- der when the variety in lipophilic components is taken into consideration [4]. Such a variety would be very difficult to handle if brains of mammals and birds did not express the same four major structures (GM1, GD1a, GD1b and GT1b) which make up high 97 % of gangliosides in, for exam- ple, human brain [5]. Gangliosides biosynthesis starts in the endoplas- matic reticulum and finishes by stepwise addition of single carbohydrate residues by glycosylation machi- nery in the Golgi complex [6]. Glycosyltransferases act in succession along Golgi-compartments (Fig. 1). Some of them compete for common specific acceptors and/or generate more than one product. The cellular pattern of gangliosides is dependent on available activated sugars, expression and the balance between the activities of the competing glycosyltransferases [7]. Changes in the ste- ady state concentration of cellular gangliosides can be predicted by the multienzyme kinetic analysis [8, 9]. Gangliosides bind side by side to different receptors [10, 11] as a part of lipid shell [12], performing «chape- rone-like» effect, probably already in Golgi apparatus. Once transported to the cell surface gangliosides become a privileged partner of cholesterol in lipid rafts modulating activities of plasma membrane proteins or participating in intercellular interactions [13]. Gangliosides in vertebrate evolution. Since glyco- sphingolipids are present in ten times higher concen- trations in the brain than in any other extraneural tissue, it was assumed that nervous tissues require some par- ticular functions served by each known ganglioside. It was likewise assumed that the functions were intro- duced with some order during the evolution. The first surveys of interspecies differences described a great variation in quantity and pattern of gangliosides in vertebrates [14, 15], particularly between different spe- cies of fish [16]. The most pronounced differences were in the quantity of lipid bound sialic acid per gram of fresh tissue between lower and higher vertebrates. While in fish brain quantities were between 110 and 750 mg/g of fresh tissue [17], in mammals they were between 650 and 1200 mg/g [18]. If species of fish were correlated according to preferred ambient temperature, then species living in warm tropical waters, like Tilapia and Pseudotrophaeus, had three times higher concen- trations of lipid bound sialic acid [17, 19] apart from the ones living in cold waters like carp and trout [20]. The pattern of brain gangliosides is also signi- ficantly different between warm and cold-blooded ani- mals and can be correlated to the state of thermal adap- tation [21] – the lower environmental or body tempera- ture is, the more polar is the composition of brain gan- gliosides. The drastic change in brain gangliosides pat- tern between warm and cold-blooded animals was ac- companied with a difference in activities of sialotrans- ferases in ganglioside biosynthesis [22]. On the other hand the pattern of brain gangliosides in related species of teleostea, anurans, urodela or mammals, was similar [19, 23, 24]. Variations were greater between different genera than between species of the same genus. The highest quantity (34–39 %) of the most polar tetra, pen- ta and hexasialogangliosides in a vertebrate brain have been found in Antartic pearch and other Notothenoidea living below freezing point (–1.5 °C) [25], while in mammals it was between 1 and 9 % [26]. Another im- portant difference between warm and cold acclimated species was quantity of alkali-labile gangliosides. Mammalian brains had minor quantity of alkali-label gangliosides (about 5 %), warm-stenothermic cichlid fish acclimated to an ambient temperature of 28 °C have 34 %, European temperate species like carp have 53–59 %, while red-blooded Antarctic fish living be- low 0 °C could have 61–67 % [27]. Most of this biochemical data have never been fur- ther investigated with immunohistochemical methods. One recent immunohistochemical study showed an interspecies difference in the expression of GD1a in olfactory bulb and olfactory pathways of frog [28] (data in press). While Ranidae sp. from all complex gang- liosides had only GD1a expressed in the main and ac- cessory olfactory tract throughout telencephalic struc- tures transmitting olfactory clue toward amygdala (Fig. 2), the expression of the same molecule in Bufidae sp. was limited to the mitral and granule cell layer of the main olfactory tract (Fig. 3). Myelin associated glyco- protein (MAG), a possible ligand for GD1a, was exp- ressed in a different subset of fibers, which suggested the unrelated function of these molecules in the frog brain. Previous biochemical studies of Rana sp. also HEFFER-LAUC M. ET AL. 106 found GD1a [29], but migrating differently on TLC- plates than GD1a from mammalian brain, possibly be- cause of a different ceramide anchor. The same bio- chemical study found also GT1b, which was not supported with immunochemistry. Another charac- teristic of the GD1a expression in Ranidae is staining of fiber tracts, which is uncommon in mammals (compare Fig. 2 and 4). The problem of all future comparative immuno- histochemical interspecies studies would be similar: a 107 THE QUEST FOR THE GANGLIOSIDE FUNCTIONS Fig. 1. Metabolic pathways and structures of glycosphingolipids. The names of enzymes participating in biosynthesis are written below ar- rows, while the names of enzymes and proteins participating in ganglioside degradation are written above arrows. List of abbreviations: AR- SA – arylsulfatase; b-gal – lysosomal acid b-galactosidase; Cer – ceramide; CST – cerebroside sulfotransferase (sulfatide synthase); GALC – galactosylceramidase; GalNAc-T – N-acetylgalactosaminyltransferase I (GA2/GM2/GD2/GT2-synthase); GalT-I – galactosyltransferase I (lactosylceramide synthase); GalT-II – galactosyltransferase II (GA1/GM1/GD1b/GT1c-synthase); GalT-III – galactosyltransferase III (galactosylceramide synthase); GLCC – glucosylceramidase; GlcT – glycosiltransferase (glucosylceramide synthase); GM2A – GM2 activa- tor protein; HEX – b-N-acetylhexosaminidase; SA – sialic acid; SAP – saposin; ST-I – sialyltransferase I (GM3-synthase); ST-II – sialyltrans- ferase II (GD3-synthase); ST-III – sialyltransferase III (GT3-synthase); ST-IV – sialyltransferase IV (GM1b/GD1a/GT1b/GQ1c-synthase); ST-V – sialyltransferase V (GD1c/GT1a/GQ1b/GP1c-synthase); ST-VII – sialyltransferase VII (GD1a/GT1a a/GQ1ba/GP1ca-synthase) lack of antibodies toward rare ganglioside structures synthesized in different species, a difference in anti- body binding to the ganglioside epitop with a different ceramide anchor [30], alkali-labile modifications in some species [31], accessibility of epitop due to diffe rent density in the membrane and just a few well des- cribed model organisms for a big taxa like Teleostea. The role of gangliosides in the evolutionary pers- pective, after the discovery of lipid rafts [32], became more interesting than ever. Lipid rafts have been des- cribed as transient membrane domains enabling ga- thering together molecules that are taking part in recei- ving, transmitting and amplifying incoming signals [33], while sphingolipids are master regulators of their dynamics [34]. It is very likely that the most common complex ganglioside structures serve the same func- tions in the rafts of all homothermic mammals [18], because they share the same pattern of distribution (Fig. 4, unpublished results of our laboratory). The interes- ting open questions come from hibernating mammals, like dormice and hamster, who change the ration of GD1a and GT1b in favor of GT1b during winter season [35], while the change was limited just to basal brain and cortex, circumventing cerebellum. The maintenan- ce of membrane properties in Teleostea is achieved by different mechanisms, considerably varying between genera. During cold-acclimation from 20 °C to 4 °C in HEFFER-LAUC M. ET AL. 108 Fig. 3. Distribution of gangliosides GM1, GD1a, GD1b and GT1b in horizontal sections of Bufo bufo. (partially published results from our group). Expression of gangliosides was studied qualitatively using highly specific monoclonal antibodies to gangliosides GM1, GD1a, GD1b and GT1b (Seikagaku, Tokyo, Japan). The negative control was performed by omitting primary antibody (control). There were no staining with anti-GM1, anti-GD1b and anti-GT1b. The strong expression of ganglioside GD1a was just in the main olfactory tract. Black arrow points to the main olfactory tract. Fig. 2. Distribution of gangliosides GM1, GD1a, GD1b and GT1b in coronal sections of Rana esculenta brain (published results, with permission of authors). Expression of gangliosides was studied qualitatively using highly specific monoclonal antibodies to gang- liosides GM1, GD1a, GD1b and GT1b (Seikagaku, Tokyo, Japan). The negative control was performed by omitting primary antibody (control). There were no staining with anti-GM1, anti-GD1b and anti- GT1b. The strong expression of ganglioside GD1a was in the main and accessory olfactory bulb. The major projections from mitral cell layer of the main olfactory bulb i. e. medial and lateral olfactory tract strongly expressed GD1a and could be followed through medial and lateral cortices to medial septal nuclei and amygdale. List of abbreviations: Ob – olfactory bulb; aob – accessory olfactory bulb; mot – medial olfactory tract; lot – lateral olfactory tract; amy – amygdala the carp brain the concentration of phosphatidylethano- lamin in cost of phosphatidylcholine increased and the ratio of cholesterol to phospholipids decreased in just two weeks [21], but changes in the quantity of poly- sialogangliosides took six weeks [19]. In trout brain cold-acclimation produced a very different shift in gan- glioside biosynthesis – decrease of monosialoganglio- sides, slight increase in di- and trisialogangliosides and no changes in polysialogangliosides [36]. Lipid rafts in thermal acclimation of trout pass through a composi- tional change not just varying in sphingolipids but also cholesterol, receptors and signaling molecules [37, 38]. When these changes happen in the brain changes in be- havior or alterations in complex processes like regene- ration might occur. Recent cloning of enzymes invol- ved in ganglioside biosynthesis in fish and amphibian brain could be the first step into this interesting field [39–41]. The role of gangliosides in brain development. The first studies of gangliosides expression in developing mammalian brain were based on lipid extraction, me- thod of variable sensitivity, producing conflicting re- sults [42–45]. The few basic concepts emerged from all studies: brain development starts with low concen- trations of simple gangliosides GM3 and GD3, comp- lex gangliosides appear with the first cortical neurons, their concentration multiplies a few times during axo- nogenesis and synaptogenesis, reaches the plateau with myelination and then is maintained through adulthood [46]. Early studies also showed that while the quantity of simple gangliosides like GM3 and GD3 decreases rapidly during development, the quantity of complex gangliosides increases with complex gangliosides of «c-pathway» and shifts toward «b» and finally «a- pathway» [46]. The observed shift in the synthesis is not connected with the exchange in the expression of two key gly- cosyltransferases (Fig. 1), ST-II (GD3-synhase) and N-acetylgalactosaminyltransferase (GalNAcT, GM2/ GD2 synthase), but with a posttranslational proces- sing and complex formation between existing trasfera- ses [9]. In that time biochemical studies were poor in distinguishing the classes of neurons or even layers of the cortex, but studies of adult brain at least established the idea of a regional pattern identity [47, 48]. There were a few attempts to understand laminar distribution of gangliosides like inventive study of a particularly en- larged «subplate layer» in the human fetal neopallium at 28 weeks of gestation [49] and developmental studi- 109 THE QUEST FOR THE GANGLIOSIDE FUNCTIONS Fig. 4. Distribution of gangliosides GM1, GD1a, GD1b and GT1b in sagittal sections of selected mammalian brains: bat, ferret, rabbit and cat (unpublished results from our group). Expression of gangli- osides was studied qualitatively using highly specific monoclonal antibodies to gangliosides GM1, GD1a, GD1b and GT1b (Seika- gaku, Tokyo, Japan). In all studied animals anti-GM1 stains fiber tracts. In ferret and cat brain GM1 is also in all or just deep layers of cortex. All studied mammals express GD1b in layers of cortex and fiber tracts, while GD1a and GT1b give mostly neuronal staining Fig. 5. Distribution of c-series gangliosides stained with Q211 anti- body in horizontal sections of 23-week-old human fetal cerebrum (published results, reproduced with permission of authors): A – im- munoreactivity was within thalamocortical fibers (asterix) exten- ding from the thalamus through the internal capsule into the inter- mediate zone; B – enlargement of cortical wall. Immunoreactivity was localized to intermediate and subplate zones, just below nega- tive cortical plate. The arrowhead marks the border between the in- termediate and subplate zone and arrow marks the border between the intermediate and subventricular zone. List of abbreviations: cp – cortical plate; ge – ganglionic eminence; ic – internal capsule; iz – intermediate zone; p – putamen; t – thalamus; sp – subplate zone es of mutant mice missing particular neuronal subpopu- lation [50, 51]. More precise determination of regional and cellular distribution had to wait for the production of anti-ganglioside antibodies, which turned out to be a very challenging task because ubiquitously presented gangliosides were not highly immunogenic. Beside dramatic changes in the synthesis of com- plex gangliosides development is accompanied with the appearance of some minor structures like «c-series» polysialogangliosides [52, 53], lactotetraose series [54] and 9-O-acetylated gangliosides [55]. These minor structures are much more immunogenic and the first high affinity antibody was raised against «c-series» po- lysialogangliosides [56]. Immunohistochemical studies [56] and particularly the use of this antibody in cell cultures [57] suggested the role of polysialoganglio- sides in axon fasciculation, migration and aggregation. The same series is present in the human brain (Fig. 5) in a transient fetal structure [58] characteristically enlar- ged in humans [59]. In the next few years antibodies against all major [60] and some of minor gangliosides [61, 62] of the bra- in were raised. Finally, it was possible to see distribu- tion of each ganglioside in adult [62–64] and develo- ping brain [65]. However, the results were providing vague clues about a distinct function. The misunder- standing was partially caused by the specificity of in- dividual antibodies [66–68], other in the difference of fixation methods [69] and one, much unexpected, came from the use of detergents [70–72]. It seemed that the problem of specificity was finally solved with the production of highly specific mouse IgG antibodies for complex gangliosides raised in Galgt1 knockout mouse [73], deficient in synthesis of complex gangliosides. Antibodies were highly specific, but still inefficient in some cases. In the case of ganglioside antibodies target recognition is defined by fine specificity of antibody and ganglioside orientation/exposure in the tissue [74]. Recently it is possible to overcome the limitations of immunohystochemistry using imaging mass spectro- metry technology [75]. As the quantity and the pattern of gangliosides in brain by itself does not imply the function, researchers turn to a more flexible model – neuronal cell cultures. In 1995 a group of researchers [76] noted that the inhibition of sphingolipid synthesis with the inhibitor of glucosyceramide synthetase D-threo-1-phenyl-2-de- canoylamino-3-morpholino-1-propanol (PDMP) wo- uld affect the length of axons and branching. Their later work showed that major changes in ganglioside syn- thesis occurred during axonogenesis and axon elon- gation, but not during dendrite growth or synaptoge- nesis [77]. At the same time the first glycosphingolipid receptors of axonal membrane, GD1a and GT1b, were discovered interacting with MAG on oligodendrocyte [78]. Differently from gangliosides, MAG appears at the final stages of development and its biding to gan- gliosides promotes axon-myelin stability and inhibits axon outgrowth after injury [79]. Such a developmen- tally late interaction has no impact on brain develop- ment and even has very mild neurological progress, which caused confusion when the first B4galnt1 or GM2/GD2 synthase knockout mice appeared with a block in the synthesis of complex gangliosides [80]. To make it even more complicated, the total brain gan- glioside concentration in these mice is the same as in the wild-type mice and one of simple gangliosides (GM3) interacts with MAG, further protracting onset of Wallerian degeneration [81, 82]. The story of B4galnt1 mice made researchers more alert to the unexpected knockout mouse phenotype. Just one of all generated knockout mice for ganglioside biosynthesis, UDP-glucose ceramide glucosyltransfe- rase, was embryonic lethal [83]. It was not surprising because it is the enzyme leading to the synthesis of all major complex gangliosides, but deserved closer look to understand if lethality was caused by neurological reasons. It turned out that conditional knockouts for the same gene in neuronal and glial cells were not embryo- nicaly lethal, but either displayed abnormal behavior by 2–3 months of age [84] or died after the onset of myelination [85], both with abnormalities and a loss of Purkinje cells. Knockouts defective for «b-series» gangliosides (GD3 synthase) are without phenotype, while double knockout of this mice and B4galnt1 have high mortality rate due to audiogenic seizures [86]. The major role of gangliosides in the nervous sys- tem is maintenance of the neuronal function in the adulthood. Such a role does not seem to be of high im- portance, but in fact maintenance makes all complex systems sustainable. Imagine a house without mainte- nance, how long would it last. Imagine how much ener- HEFFER-LAUC M. ET AL. 110 gy would be lost if you had to rebuild the house on regular basis just because you are not able to perform maintenance. In case of perfectly operational mainte- nance, you are able to give up some expensive, com- plicated or very slow functions, like for example rege- neration. Gangliosides are just one of cellular mecha- nisms serving at cell membranes in maintenance of lipid rafts [87], lubricating signaling pathways [88] and chaperoning a number of cell proteins [11]. Ì. Õåô ôåð-Ëàóê, À. Ìîæ ñî âè÷-×ó³ê, Á. ³ëüæå òè÷, Ä. Äè êè÷ Ïî øóê ôóíêö³é ãàíãë³îçèä³â; ùî íî âî ãî ìè ä³çíà ëè ñÿ ç «evo-devo», àáî ñèã íàë³íã äîâ ãîò ðè âà ëî ãî çáå ðå æåí íÿ Ðåçþìå Ãàíãë³îçè äè – õà ðàê òå ðèñ òè÷í³ äå òåðì³íà íòè, ÿê³ ëî êàë³çî - âàí³ íà çîâí³øí³é ïî âåðõí³ ìåì áðàí êë³òèí ìîç êó õðå áåò íèõ. ×î òè ðè îñíîâ íèõ ãàíãë³îçè äè (GM1, GD1a, GD1b i GT1b) ïå ðå - âà æà þòü ñå ðåä ñî òåíü ³íøèõ ñïî ëóê ãë³êîë³ï³ä³â íå ðâî âî¿ òêà - íè íè. Ó ïðî öåñ³ ðîç âèò êó ìîç êó åêñïðåñ³ÿ ïðî ñòèõ ãàíãë³îçèä³â çì³ùóºòüñÿ ó á³ê ñèí òå çó á³ëüø ñêëàä íèõ ñïî ëóê, ùî ñóï ðî âîä - æóºòüñÿ áà ãà òî ðà çî âèì çðîñ òàí íÿì ¿õíüî¿ çà ãàëü íî¿ ê³ëü- êîñò³. Çì³ùåí íÿ åêñïðåñ³¿ – ñòðî ãî ðå ãóëü î âà íèé ïðî öåñ, çà ÿêîãî ïî ÿ âà äå ÿ êèõ ñïå öèô³÷íèõ ñòðóê òóð ðåï ðå çåí òóº äîá ðå â³äîì³ ñòà䳿 ðîç âèò êó íå ðâî âî¿ òêà íè íè. Ç òî÷ êè çîðó åâî - ëþö³¿ âì³ñò ãàíãë³îçèä³â ó ìîç êó ðèá òà àìô³á³é çíà÷ íî íèæ- ÷èé, í³æ ó ìîç êó ññàâö³â, ïðî òå çà ãàëü íà ¿õíÿ âàð³àáåëüí³ñòü ñóòòºâî âèùà. Á³ëüø ïî ëÿðí³ ñïî ëó êè, ÿê³ øè ðî êî ïðåä ñòàâ ëåí³ ó àí òàð êòè÷ íèõ ðèá, º ð³äê³ñíè ìè äëÿ ññàâö³â àáî õà ðàê òåð íè - ìè äëÿ ïåâ íî ãî êî ðîò êîò ðè âà ëî ãî åòà ïó îíòî ãå íå çó. Ïëà çó íè, ïòà õè ³ ññàâö³ çáåð³ãà þòü ³äåí òè÷í³ ñï³ëüí³ ñòðóê òó ðè, ùî ìà - þòü ïîä³áí³ ïà òåð íè åêñïðåñ³¿ ç íå çíà÷ íè ìè ì³æâè äî âè ìè â³äì³ííîñ òÿ ìè. Íàâ ïà êè, äëÿ ìîç êó ðèá òà àìô³á³é â³äçíà ÷å íî ³ñòîò íó ì³æâè äî âó â³äì³íí³ñòü ùîäî ê³ëüêîñò³, ñòðóê òó ðè òà ïà òåð íó åêñïðåñ³¿. Ïåð øî ÷åð ãî âèì ïðè ïó ùåí íÿì åâî ëþ- ö³éíî ãî äîñë³äæåí íÿ ñòà ëî òå, ùî âàð³àö³¿ ó âì³ñò³ ë³ï³ä³â, çîê - ðå ìà ãë³êîë³ï³ä³â, ï³ä ÷àñ òåì ïå ðà òóð íî¿ àäàï òàö³¿ ó õî ëîä íîê - ðîâ íèõ ³ ãå òå ðî òåð ìíèõ òâà ðèí, ÿê³ âïà äà þòü ó ñïëÿ÷ êó, º âè- ñî êî å ôåê òèâ íèì ìî ëå êó ëÿð íèì ìå õàí³çìîì çà õèñ òó ôóíêö³î- íó âàí íÿ ìåì áðàí. Âèâ ÷åí íÿ âïî ðÿä êî âà íèõ äî ìåí³â ë³ï³ä³â çà îñòàííº äå ñÿ òèë³òòÿ ï³äòâåð äæóº ãàíãë³îçèä-îïî ñå ðåä êî âà - íó ðå ãó ëÿö³þ ìåì áðàí íèõ á³ëê³â (ðå öåï òî ðè ç ê³íà çíîþ àê - òèâí³ñòþ, ðå öåï òî ðè íå é ðîò ðàíñì³òåð³â òà ³îíí³ êà íà ëè), òàê ñàìî ÿê ³ âçàºìîä³þ ðå öåï òîð–ë³ãàíä, âàæëèâó äëÿ ïå ðå - äà÷³ ïî çàêë³òèí íî ãî ñèã íà ëó. Êëþ ÷îâ³ ñëî âà: ãàíãë³îçè äè, ãî ëîâ íèé ìî çîê, åâî ëþö³ÿ, ðîç - âè òîê, êë³òèí íà ñèã íàë³çàö³ÿ, lipid rafts. Ì. Õåô ôåð-Ëàóê, À. Ìîæ ñî âè÷-×óèê, Á. Âèëü æå òè÷, Ä. Äè êè÷ Ïîèñê ôóíê öèé ãàí ãëè î çèäîâ; ÷òî íî âî ãî ìè óçíà ëè èç «evo-devo», èëè ñèã íà ëèíã äëè òåëü íî ãî ñî õðà íå íèÿ Ðå çþ ìå Ãàí ãëè î çè äû – õà ðàê òå ðèñ òè ÷åñ êèå äå òåð ìè íàí òû, ëî êà ëè çî - âàí íûå íà âíåø íåé ïî âåð õíîñ òè ìåì áðàí êëå òîê ìîç ãà õðå áåò - íûõ. ×å òû ðå îñíîâ íûõ ãàí ãëè î çè äà (GM1, GD1a, GD1b è GT1b) ïðå îá ëà äà þò ñðå äè ñî òåíü äðó ãèõ ñî å äè íå íèé ãëè êî ëè ïè äîâ íå ðâíîé òêà íè.  ïðî öåñ ñå ðàç âè òèÿ ìîç ãà ýêñ ïðåñ ñèÿ ïðî ñòûõ ãàí ãëè î çè äîâ çà ìå ùà åò ñÿ ñèí òåçîì áî ëåå ñëîæ íûõ ñî å äè íå - íèé, ÷òî ñî ïðî âîæ äà åò ñÿ ìíî ãîê ðàò íûì óâå ëè ÷å íè åì èõ îá - ùå ãî êî ëè ÷åñ òâà. Ñìå ùå íèå ýêñ ïðåñ ñèè – ñòðî ãî ðå ãó ëè ðî âàí- íûé ïðî öåññ, ïðè êî òî ðîì ïî ÿâ ëå íèå íå êî òî ðûõ ñïå öè ôè ÷åñ - êèõ ñòðóê òóð ïðåä ñòàâ ëÿ åò õî ðî øî èç âåñ òíûå ñòà äèè ðàç âè - òèÿ íå ðâíîé òêà íè. Ñîäåð æà íèå ãàí ãëè î çè äîâ â ìîç ãå ðûá è àì ôè áèé çíà ÷è òåëü íî íèæå, ÷åì â ìîç ãå ìëå êî ïè òà þ ùèõ, îäíà êî èõ îá ùàÿ âà ðè à áåëü íîñòü ñó ùåñ òâåí íî âûøå. Áî ëåå ïî - ëÿð íûå ñî å äè íå íèÿ, øè ðî êî ïðåä ñòàâ ëåí íûå ó àí òàð êòè ÷åñ êèõ ðûá, ÿâ ëÿ þò ñÿ ðåä êè ìè äëÿ ìëå êî ïè òà þ ùèõ èëè õà ðàê òåð íû - ìè äëÿ îïðå äå ëåí íî ãî êðàò êîâ ðåìåí íî ãî ýòà ïà îíòî ãå íå çà. Ïðåñ ìû êà þ ùè å ñÿ, ïòè öû è ìëå êî ïè òà þ ùèå ñî õðà íÿ þò îá ùèå èäåí òè÷ íûå ñòðóê òó ðû ñ ïî äîáíûìè ïàò òåð íà ìè ýêñ ïðåñ ñèè, èìå þ ùè ìè íå çíà ÷è òåëü íûå ìåæ âè äî âûå îò ëè ÷èÿ. Íà î áî ðîò, äëÿ ìîç ãà ðûá è àì ôè áèé îò ìå ÷å íû ñó ùåñ òâåí íûå ìåæ âè äî - âûå îò ëè ÷èÿ, êà ñà þ ùè å ñÿ êî ëè ÷åñ òâà, ñòðóê òó ðû è ïàò òåð íà ýêñ ïðåñ ñèè. Ïåð âî î ÷åðåäíûì ïðåä ïî ëî æå íè åì ýâî ëþ öè îí íî ãî èñ ñëå äî âà íèÿ ñòà ëî òî, ÷òî âà ðè à öèè â ñî äåð æà íèè ëè ïè äîâ, â ÷àñ òíîñ òè ãëè êî ëè ïè äîâ, âî âðå ìÿ òåì ïå ðà òóð íîé àäàï òà öèè ó õëàä íîê ðîâ íûõ è ãå òå ðî òåð ìíûõ æè âîò íûõ, âïà äà þ ùèõ â ñïÿ÷ êó, ÿâ ëÿ þò ñÿ âûñî êî ýô ôåê òèâ íûì ìî ëå êó ëÿð íûì ìå õà - íèç ìîì çà ùè òû ôóíê öè î íè ðî âà íèÿ ìåì áðàí. Èçó ÷å íèå óïî ðÿ - äî ÷åí íûõ äî ìå íîâ ëè ïè äîâ çà ïî ñëåä íåå äå ñÿ òè ëå òèå ïîä òâåð æäà åò ãàí ãëè î çèä-îïîñ ðå äî âàí íóþ ðå ãó ëÿ öèþ ìåì - áðàí íûõ áåë êîâ (ðå öåï òî ðû ñ êè íàç íîé àê òèâ íîñ òüþ, ðå öåï - òî ðû íå é ðîò ðàí ñìèò òå ðîâ è èîí íûå êà íà ëû), òàê æå êàê è âçà è ìî äå éñòâèå ðå öåï òîð–ëè ãàíä, âàæ íîå äëÿ ïå ðå äà ÷è âíåê - ëå òî÷ íî ãî ñèã íà ëà. Êëþ ÷åâûå ñëî âà: ãàí ãëè î çèäû, ãî ëîâíîé ìîçã, ýâî ëþ öèÿ, ðàç - âèòèå, êëåòî÷íàÿ ñèã íà ëè çàöèô, lipid rafts. REFERENCES 1. Woods A. S., Jackson S. N. 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