Department of Neuroscience, Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Abstract |
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Introduction |
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A central question in the study of ectopic dendritogenesis in storage diseases has been whether there are common mech- anisms underlying this disease-associated phenomenon and the sprouting of primary dendrites in normal developing brain. Studies examining cortical neurons undergoing normal and ectopic dendritic sprouting indicate that elevated expression of one specific glycosphingolipid GM2 ganglioside links these two events [reviewed by Walkley et al. (Walkley et al., 1995)]. This particular ganglioside has been found elevated in all neuronal storage diseases with ectopic dendritogenesis whereas normal mature neurons and neurons in storage diseases not characterized by ectopic dendritogenesis do not exhibit significant expression of GM2 ganglioside. Ectopic dendrito- genesis has been found to be most abundant in GM2 ganglio- sidosis, a disorder in which GM2 elevation is the direct result of a catabolic defect (Siegel and Walkley, 1994
). There is also evidence that intraneuronal elevation of GM2 ganglioside pre- cedes the outgrowth of ectopic dendrites in storage diseases (Goodman et al., 1991
). These findings are consistent with GM2 elevation being a cause, rather than a consequence, of new dendritogenesis.
In examining normal developing neurons in the same species (domesticated cat) used to document the correlation between GM2 ganglioside and ectopic dendritogenesis, it was found that a heightened expression of GM2 again correlated with dendrite outgrowth (Goodman and Walkley, 1996). That is, postmigrat- ory cortical neurons expressed GM2 ganglioside coincident with normal dendritic sprouting and, after dendritic maturation was complete in the early postnatal period, GM2 levels dropped to negligible amounts. Subsequent studies in the ferret documented not only the same correlation in this species but also showed that no other ganglioside had a similar pattern of expression (Zervas and Walkley, 1999a
). In the present study we compare these findings with an examination of GM2 expression in developing human cerebral cortex during normal dendritogenesis, and with an evaluation of murine models of neuronal storage diseases for GM2 expression and ectopic dendrite growth.
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Materials and Methods |
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Brain tissue also was obtained from three murine models of GM2 gangliosidosis: Tay-Sachs disease or -subunit knockout (Yamanaka et al., 1994
), Sandhoff disease or ß-subunit knockout (Sango et al., 1995
) and a combined
ß double knockout (Sango et al., 1996
). A murine model of Niemann-Pick disease type A (Horinouchi et al., 1995
) also was evaluated by Golgi and immunocytochemical methods. This disorder in humans is known to exhibit secondary elevation of gangliosides (Kamoshita et al., 1969
) and a feline model of this disease has been found to exhibit ectopic dendritogenesis (Walkley and Baker, 1984
). Access to the mouse models of storage diseases was generously provided by Drs R. Proia, E. Schuchmann and K. Suzuki. Animals were deeply anesthetized with pentobarbital and tissues fixed by intracardiac perfusion with 4% paraformaldehyde, followed by 24 h of immersion fixation and sub- sequent storage at 4°C in PB.
Rapid Golgi staining was carried out on human and murine tissues according to published methods (Zervas and Walkley, 1999a). Immuno- cytochemical studies used an antibody to GM2 ganglioside (generously provided by P. Livingston) and peroxidase labeling carried out on 35 µm Vibratome sections according to previously published methods (Walkley, 1995
; Zervas and Walkley, 1999a
). Results of Golgi and immunocyto- chemical staining on normal human brain were compared with earlier studies on cortical development in the cat (Goodman and Walkley, 1996
) and the ferret (Zervas and Walkley, 1999a
). Data from murine models of storage diseases were compared with our earlier studies on storage diseases in animal models [reviewed by Walkley (Walkley, 1998
)] and with archival material kindly provided by Drs D. Purpura and K. Suzuki.
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Results |
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Nissl staining of human cortical tissues at 16 weeks of gestation revealed the presence of specific cell layers consistent with previous studies at this stage of development in the human brain (Honig et al., 1996; Marin-Padilla, 1970
, 1992
). The undiffer- entiated cortical plate (uCP), a compact layer of undifferentiated neurons, was found immediately beneath the superficial and cell-sparse marginal zone (MZ). Immediately below the uCP was a 300-µm-wide band of differentiating cortical plate (CP) neurons representing presumptive layers VVI (Figure 1A
). Golgi staining of this area revealed the presence of bipolar neurons, many of which exhibited small neuritic sprouts from perikarya and proximal portions of the apical and basilar processes (Figure 1B
). Below this layer of differentiating CP neurons was the subplate (SP), a broad band of cells ~800 µm wide. The SP appeared somewhat denser in its upper half and consisted of vertically elongated cells (presumptive migratory neurons) interspersed with other cells of more rounded and/or nonvertical orientation. Myelinated axons were seen traversing the area beneath the SP and above the dense palisades of cells of the ventricular zone (VZ). Immunocytochemical staining for GM2 ganglioside revealed fine punctate structures in cells immediately beneath the uCP and more conspicuous immunoreactive punctae in presumptive layers V/VI just above the SP (Figure 1C
). The SP, as well as the MZ, revealed occasional GM2-immunoreactive cells which appeared principally rounded and with multiple processes.
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Golgi staining in mouse models of GM2 ganglioside storage diseases (Tay-Sachs, Sandhoff and double knockouts) and in Niemann-Pick disease type A revealed occasional swollen axon hillocks and small aspiny meganeurites, but most neurons appeared essentially normal in somaticdendritic morphology (Figure 4AC). At most, an occasional short spine-like protrusion was observed at the axon hillock region of mouse pyramidal neurons. The absence of ectopic dendrite growth did not seem to be due to longevity of the disease state since cats living to ages equivalent to those of mice with the same disease (e.g. Sandhoff and Niemann-Pick type A diseases) exhibited significant numbers of axon hillock neurites. There was also no absence of GM2 immunostaining in cortical neurons as each of the mouse models examined in this study exhibited conspicuous elevations of this ganglioside in pyramidal neuron perikarya (Figure 4
DF). In contrast to these findings, cortical pyramidal neurons in human storage diseases (Purpura and Suzuki, 1976
) and in non-rodent animal models [reviewed by Walkley (Walkley, 1998
)] exhibited prolific dendrite growth (Figure 5
). Dendritic neurites emerged from axon hillocks and/or from meganeurites and, particularly in human diseases, these processes often possessed spines and resembled the adjacent normal basilar dendrites. The presence of ectopic dendrites in storage diseases in humans and non-rodent animal models correlated closely with an accumulation of GM2 ganglioside. In contrast, normal mature neurons in all species revealed little or no GM2 immuno- reactivity (Siegel and Walkley, 1994
; Walkley, 1995
).
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Discussion |
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Studies of human cortical development reported here provide additional evidence in support of the link between GM2 ganglioside expression and dendritic sprouting. The presence of robust GM2 immunoreactivity in human cortical neurons during dendritic differentiation was remarkably similar to that reported in the cat and ferret. For these species, GM2 expression was first observed at the time of initial dendrite outgrowth on lower CP pyramidal neurons, spread into more superficial layers as they formed and then diminished as dendritic arbors became fully established in the early postnatal period (Goodman and Walkley, 1996; Zervas and Walkley, 1999a
). Thus, for human and other non-rodent brain tissue, during both normal development and in storage diseases, the correlation between GM2 ganglioside expression and dendritogenesis is remarkably consistent. The relationship between gangliosides and dendritogenesis in the rodent brain, however, will require additional study. Rodent cortical neurons in culture have been shown to transiently express GM2 ganglioside during dendrite outgrowth, but appear to exhibit less GM2 immunoreactivity than ferret cultures under similar conditions (K. Dobrenis et al., unpublished data). Similarly, high-performance thin-layer chromatography analysis has revealed a lower level of expression of gangliosides in the mature rodent brain, based on both dry weight and cell number, in comparison with the human brain (Hess et al., 1976
). Absence of demonstrable ectopic dendrite growth in murine storage disease models suggests possible significant differences in post- natal mechanisms controlling dendritic plasticity, or alternatively, in the role of gangliosides in normal dendritic differentiation in this species.
The consistent correlation between intraneuronal elevation of GM2 ganglioside and outgrowth of primary dendrites on cortical pyramidal neurons in humans and other non-rodent species raises the question of how a glycosphingolipid might function to influence dendritogenesis. Gangliosides are sialic-acid-contain- ing glycolipids found in many cell types and organs but enriched in brain. In spite of considerable investigation, the function of gangliosides is not well understood. Early studies focused on these molecules as possible receptors, but the current prevailing view is that they more likely act as modulators of receptors and/ or their second messenger cascades (Hakomori, 1990, 1995
; Zeller and Marchase, 1992
; Yates and Rampersaud, 1998
). Fluctuation in expression of individual types of gangliosides and/or their synthetic enzymes during brain development has been cited as evidence of their importance during this period (Tetamanti, 1971
; Vanier et al., 1971
; Yu et al., 1988
; Skaper et al., 1989
; Yamamoto et al., 1996
). Although GM2 ganglioside has rarely been part of these studies, it has been described as an oncofetal antigen since it was found to occur in certain tumors and in human fetal brain with peak expression at 22 weeks gestation (Irie et al., 1976
; Tai et al., 1983
).
Gangliosides are known to be synthesized sequentially in the Golgi/trans-Golgi network (TGN) by a series of membrane- bound glycosyltransferases, and individual gangliosides are believed to be transported to the plasmalemma by exocytic vesicles where they are inserted into its outer leaflet (Yusuf et al., 1984; Sandhoff and Schwarzmann, 1989
) (Figure 6A
). Little is currently known about the control of ganglioside synthesis, the mechanisms of differential transport of gangliosides away from the Golgi or the process of somaticdendritic exocytosis. Consistent with the proposed scheme for ganglioside synthesis and trafficking, ultrastructural studies of immature human cor- tical neurons, as well as of those of the cat and ferret, show the presence of GM2-immunoreactive vesicles in close association with the Golgi/TGN, within the somaticdendritic cytoplasm and near the plasmalemma. GM2-laden vesicles were not found to be present in axons of any of the species investigated. Whether GM2-labelled vesicles within neuronal perikarya con- tain other molecules destined for the cell surface is unknown. However, recent studies have suggested that calcium-evoked exocytic activity in dendrites of hippocampal neurons plays a role in dendritic plasticity through delivery of postsynaptic membrane and plasmalemmal proteins (Maletic-Savatic and Koothan, 1998; Maletic-Savatic and Malinow, 1998
).
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Although ganglioside function remains largely enigmatic, studies in recent years offer possible insights into how they might affect signaling across cell membranes. Implicated in these studies are possible associations between gangliosides and glycosylphosphatidylinositol (GPI)-anchored proteins, signal transduction molecules and growth factor receptors (Figure 6B). Gangliosides and other glycosphingolipids, in association with cholesterol, are believed to form lipid microdomains or rafts in the plasmalemma and to act as platforms for the attachment of proteins involved in signal transduction (Simons, 1997; Brown and London, 1998
; Jacobson and Dietrich, 1999
; Prinetti et al., 1999
). Studies have shown that signaling molecules implicated in dendritogenesis, including GPI-anchored proteins, tyrosine kinases of the Src family and receptor tyrosine kinases (Trks), may be associated with these raft structures (Wu et al., 1997
) [reviewed by Brown and London (Brown and London, 1998
)]. As neurons mature and ganglioside expression patterns change during development, it is likely that the ganglioside constituents of lipid rafts would also change, leading to developmentally linked differences in raft function.
Transport and sorting of raft-associated GPI-anchored proteins from the Golgi/TGN to the plasmalemma may be dependent on an interaction with glycosphingolipids [reviewed by Futerman (Futerman, 1995)]. Evidence for such coupling is based on altered transport of GPI-anchored proteins secondary to inhibition of GSL synthesis. One type of GPI-anchored protein in neurons, CPG15, has recently been shown to be associated with dendritic sprouting (Nedivi et al., 1998
; Corriveau et al., 1999
). A product of candidate plasticity gene 15 (cpg15), this protein is located on the cell surface of Xenopus neurons, where it is believed to function in an activity-dependent manner to enhance dendritic complexity. A truncated form of CPG15 (neuritin) also has been associated with neurite outgrowth in rat brain, and neuritin mRNA expression is increased by treatment with brain-derived neurotrophic factor (BDNF) and other neurotrophins, as well as by neuronal activity (Naeve et al., 1997
; Corriveau et al., 1999
). In parallel to the Xenopus studies, overexpression of neuritin in rat hippocampal and cortical neurons caused enhanced neuritic outgrowth.
Gangliosides have been reported to be associated in rafts with signal transduction molecules like small GTPases and nonreceptor tyrosine kinases (Figure 6B). For example, GM3 ganglioside has been found in rafts containing Rho-A and c-Src in a melanoma cell line (Yamamura et al., 1997
). This same ganglioside co-immunopurifies with the GPI-anchored surface glycoprotein CD59 and Src-family protein-tyrosine kinases in leukocytes (Kniep et al., 1994
). The Src-family kinase Lyn has been found in rat brain to immunoprecipitate with GD3 ganglio- side (Kasahara et al., 1997
) and in rat basophilic leukemia cells with GD1b (Minoguchi et al., 1994). As with the GPI-anchored protein CPG15, some of these second messengers have also been reported linked to dendritogenesis (Chen et al., 1996
). Overexpression in immature rat cortical neurons of certain small GTPases (Rho-A, as well as Rac and Cdc42) leads to an increase in the number of primary dendritic sprouts (Threadgill et al., 1997
). Additionally, some of these same GTPases have been implicated in the control of dendritogenesis in neurons of Drosophila (Cdc42) (Gao et al., 1999
) and in retinal cells of Xenopus (Cdc42 and Rac1) (Ruchhoeft et al., 1999
).
In addition to the above studies, other reports suggest that gangliosides in the outer membrane leaflet of the plasmalemma are in functional association with receptor tyrosine kinases (Figure 6B). It has been reported that gangliosides modify the function of these receptors by affecting receptor dimerization, tyrosine phosphorylation and/or their downstream signaling cascades, and that different gangliosides may have graded or even opposite effects [reviewed by Bremer and by Yates and Rampersaud (Bremer, 1994
; Yates and Rampersaud, 1998
)]. For example, several types of gangliosides have been shown to inhibit dimerization of the platelet-derived growth factor recep- tor as well as the kinase activity of this receptor in several cell types (Hynds et al., 1995
; Yates et al., 1995
; Sachinidis et al., 1996
). GM1 ganglioside has been shown in immunoprecipi- tation studies to be closely associated with TrkA and to augment NGF-stimulated neurite outgrowth (Mutoh et al., 1995
; Rabin and Moccheti, 1995; Farooqui et al., 1997
). Similar studies have shown that GM1 enhancement of dimerization of TrkA receptors promotes survival of PC12 cells after withdrawal of trophic support (Ferrari et al., 1995
). GM1 ganglioside has also recently been implicated in dimerization and tyrosine phosphorylation of TrkB in cultured cerebellar granule cells (Pitto et al., 1998
). Studies linking individual types of Trks and gangliosides may be of particular relevance since the neurotrophins BDNF and NT4 (ligands for TrkB) have been reported to cause exuberant dendritogenesis when applied to immature cortical neurons (McAllister et al., 1995
, 1996
). Based on these and related reports, neurotrophins have emerged as likely pivotal elements in morphological and synaptic plasticity in the brain (McAllister et al., 1999
).
From the above discussion it can be seen that three types of experimental manipulations involving mammalian cortical neurons result in an exuberant sprouting of primary dendrites. These involve the overexpression in rat cortical neurons of the GPI-anchored protein, neuritin (Naeve et al., 1997), and of Rho- family GTPases (Threadgill et al., 1997
), and the application of TrkB ligands to ferret cortical slices (McAllister et al., 1995
). There is also a fourth example whereby mammalian cortical neurons have been experimentally manipulated to undergo new dendritic sprouting. This study utilized the indolizadine alkaloid, swainsonine, to inhibit lysosomal
-mannosidase and induce a phenotypic replica of genetic
-mannosidosis in young adult cats (Walkley et al., 1988
). As a result, pyramidal neurons in layers III and V accumulated GM2 ganglioside and underwent ectopic dendritic sprouting identical to inherited
-mannosidosis. The first three studies cited above involved immature neurons manipulated in vitro at a time when they were undergoing normal dendritic differentiation, whereas the swainsonine study involved fully mature postnatal neurons studied in vivo. Induc- tion of dendritic sprouting following overexpression of the GTPases and neuritin were suggested to be possible downstream events in a neurotrophin signalling pathway involving BDNF and TrkB (Naeve et al., 1997
; Threadgill et al., 1997
). But how might GM2 ganglioside fit into this scenario? The ferret cortical slices used in the TrkB studies by McAllister and colleagues were done at P14 a time when GM2 is enriched in these neurons (Zervas and Walkley, 1999a
). Likewise, the E17/18 dissociated rat cortical cultures showing increased dendrite outgrowth follow- ing transfection with Rho-related GTPases and with neuritin were also at a stage during treatment (37 days in vitro) when these neurons have been found to express GM2 ganglioside (Dobrenis and Walkley, 1992
). These findings, coupled with in vivo studies linking GM2 expression with both normal and ectopic dendritogenesis, are consistent with GM2 ganglioside playing a pivotal role in priming neurons for dendritic out- growth. The swainsonine model further suggests that compon- ents of a regulatory mechanism with which GM2 presumably interacts in immature neurons (during normal development) are retained to some degree in young adult neurons.
An overall view that emerges from these studies is that the initiation of primary dendrites on neurons is likely controlled by multiple layers of interrelated regulatory mechanisms, with more highly evolved neurons having simpler mechanisms overlain by additional regulatory elements. Significant differences in such mechanisms according to species, developmental age and cell type are likely. Expression of regulatory molecules may be enhanced and/or temporally prolonged in some animals (e.g. primates) and more restricted in others (e.g. rodents). Changes in expression of one regulatory element in a control mechanism may alter the function of others. Conceivably, such switching could involve the regulation of dendritic sprouting at one stage of development and control over other aspects of dendritic plasticity at later stages. Understanding how such mechanisms initially craft and then maintain the unique dendritic arbors displayed by individual types of neurons likely will require attention not only to growth factors and their receptors, related membrane proteins and second messenger systems, but also to the specific glycolipid microenvironment of the membranes in which these molecules reside.
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Notes |
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Address correspondence to Steven U. Walkley, Department of Neuro- science, Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA. Email: walkley{at}aecom.yu.edu.
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