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Cellular and Molecular Mechanisms of Dendrite Growth A. Kimberley McAllister Proper growth and branching of dendrites are crucial for nervous system function; patterns of dendritic arborization determine the nature and amount of innervation that a neuron receives and specific dendritic membrane properties define its computational capabilities. Until recently, there was relatively little known about the cellular and molecular mechanisms of dendritic growth, perhaps because dendrites were historically considered to be intrinsically determined, passive elements in the formation of connections in the nervous system. In the last few years, however, overwhelming evidence has accumulated indicating that dendritic growth is remarkably dynamic and responsive to environmental signals, including guidance molecules and levels and patterns of activity. This manuscript reviews our current understanding of the cellular and molecular mechanisms of dendritic growth, the influence of activity in sculpting specific patterns of dendritic arbors, and a potential integral role for dendrites in activity-dependent development of circuits in the nervous system. historically, dendrites were believed to be intrinsically determined, passive elements in the formation of connections in the nervous system, evidence is rapidly accumulating that dendrites are remarkably responsive to environmental signals. Advanced imaging techniques, in particular, are revolutionizing our ideas about how dendrites grow. These imaging studies vividly show that the growth of dendrites is highly dynamic, rather than passive. Moreover, dendritic growth is locally regulated by synaptic activity and other molecular signals from neighboring cells. Activity-dependent structural changes in postsynaptic cells act together with changes in presynaptic axonal arbors to shape specific patterns of connectivity in the nervous system. Thus, the growth of dendrites is a dynamic process inf luenced by, and integral to, the formation of connections in the nervous system. The goals of this review are twofold: (i) to summarize and discuss the cellular mechanisms of dendritic growth, including evidence that dendritic growth is activity-dependent; and (ii) to describe the molecular signals discovered to date that may inf luence dendritic growth and mediate the effects of synaptic activity on dendritic development. This review primarily focuses on mechanisms of the growth of dendrites; comprehensive reviews of dendritic spine development and plasticity appear elsewhere (Harris and Kater, 1994; Harris, 1999; Frotscher et al., 2000; Geinisman, 2000). Introduction The nervous system is composed of a vast number of neurons with characteristic afferent and efferent projections, dendritic morphologies and molecular identities. In general, neurons across the nervous system exhibit type-specific patterns of dendritic arbors with highly specified membrane properties that define the computational capability of each cell (Rall, 1995; Stuart et al., 1999). As dendrites are the site of most synaptic contacts, dendritic development determines the number and pattern of synapses received by each neuron (Hume and Purves, 1981; Purves and Hume, 1981; Purves et al., 1986). Consequently, the results of defects in dendritic growth are profound, often accompanying severe neurodevelopmental disorders such as mental retardation (Purpura, 1975). Thus, the proper growth and arborization of dendrites are crucial for proper functioning of the nervous system. Nervous system development comprises several stages. First, neurons are born and migrate to their final positions in the nervous system. Subsequently, neurons elaborate their axons and dendrites in patterns characteristic for each cell type. Finally, highly specific connections between neurons — synapses — are formed. In many cases, these early synaptic connections are sculpted and remodeled by neuronal activity to achieve the mature pattern of connectivity in the brain (Goodman and Shatz, 1993; Katz and Shatz, 1996). Such precise interconnections between neurons suggest a high degree of cellular and molecular regulation during development. Although research in the past 20 years has markedly increased our general understanding of the cellular and molecular mechanisms of axonal outgrowth and pathfinding, until recently, relatively little was known about the signals that guide dendritic growth. Research into the cellular and molecular mechanisms of dendritic growth has blossomed in the last 5 years. Although, © Oxford University Press 2000. All rights reserved. Center for Neuroscience, University of California, Davis, CA 95616, USA Normal Dendritic Development From the time of Golgi and Cajal, dendritic development has been studied by observing neuronal morphology in fixed tissue at particular developmental stages. These studies concluded that dendrites grow through a steady process of extension and branching. In general, outgrowth of dendrites often occurs after the outgrowth of the axon and, in some cases, the axon may even form connections with its target before dendritic differentiation (DeFelipe and Jones, 1988). Dendritic arbors develop in a highly choreographed manner. For example, in the developing cerebral cortex, apical dendrites of pyramidal neurons form from the leading process of migrating neurons while basal dendrites sprout from the cell body in a characteristic order (Miller, 1988). First, primary basal dendrites extend directly from the cell body; higher order dendrites appear by branching from the primary dendrites. For most neuronal types, dendritic growth is slow at first but then dramatically increases with a transient overproduction of dendrites to achieve the mature dendritic arborization (Ramon y Cajal, 1911; Miller, 1988; Koester and O’Leary, 1992). In the past few years, technical advances in our ability to label and image living neurons in real-time has dramatically changed the pervading view of how dendrites grow (Dailey and Smith, 1996; Wong and Wong, 2000). Rather than the steady growth implied from studies of fixed tissue, real-time imaging has demonstrated that dendritic elaboration occurs through a net growth of highly dynamic filopodia that each extend and Cerebral Cortex Oct 2000;10:963–973; 1047–3211/00/$4.00 retract many times a minute (Dailey and Smith, 1996). Realtime imaging of dendritic growth in hippocampal slices using time-lapse confocal microscopy shows that dendritic growth is dependent on stabilization of a subset of many highly motile and protrusive dendritic structures (Dailey and Smith, 1996). Moreover, dendritic filopodia rapidly extend toward nearby axonal growth cones to form synaptic connections, implying that dendrites may be a much more active force in synapse formation than previously imagined (Cooper and Smith, 1992; Ziv and Smith, 1996; Jontes et al., 2000). Many dendritic filopodia make synapses with presynaptic axons (Papa et al., 1995; Fiala et al., 1998). As the neurons mature, these filopodia become much less dynamic and eventually retract into the dendritic shaft just before dendritic spines are formed (Dailey and Smith, 1996; Fiala et al., 1998). Thus, dendritic filopodia may serve to increase the likelihood of synapse formation and to physically pull axons toward the dendrite. As the neuron matures, dendritic spines with characteristic morphologies are formed (Harris, 1999). Although these spines have classically been considered stable structures, recent imaging experiments clearly demonstrate that spines undergo rapid structural alterations in response to synaptic activity (Fischer et al., 1998; Engert and Bonhoeffer, 1999). The final form and extent of dendritic arbors result from interactions between intrinsic developmental programs and local environmental cues, including levels and patterns of activity. Historically, dendrites were considered to be wholly intrinsically determined. In support of this idea, all neurons have an intrinsic ability to produce branched dendrites. This is clearly demonstrated by isolated neurons in culture. The general features of dendritic morphology of isolated, cultured neurons are conserved; remarkably, it is possible to identify the type and original location of cultured neurons based on their general shape (Bray, 1973; Banker and Cowan, 1979; Bartlett and Banker, 1984). However, cultured neurons rarely exhibit the extent of dendritic complexity as occurs in vivo, suggesting that environmental signals work with intrinsic mechanisms to regulate proper dendritic arborization. In fact, evidence for a potent role for environmental signals, including neuronal activity, in regulating dendritic growth is overwhelming. The Role of Activity in Dendritic Growth Electrical activity of neurons shapes patterns of synaptic connectivity during early development of the nervous system (Katz and Shatz, 1996). Although most studies have focused on the role of activity in sculpting axonal arbors, there is increasing evidence that neuronal activity also fine-tunes dendritic growth and branching. Dendritic differentiation occurs concurrently with synapse formation, suggesting that afferent axon terminals might stimulate dendritic growth. In general, most neurons must receive a particular level and/or pattern of afferent activity for characteristic adult patterns of dendrites to develop. In some areas of the nervous system, the number of afferents can even determine the size and complexity of dendritic arbors. For example, the number of dendrites of ciliary ganglion neurons is directly proportional to the number of innervating axons (Purves and Hume, 1981). In addition, the number of dendrites of superior cervical ganglion neurons is also related to the size of the neuron’s target (Purves and Lichtman, 1985; Voyvodic, 1989). 964 Mechanisms of Dendrite Growth • McAllister Changing Overall Levels of Neuronal Activity Alters Dendritic Arborization Decreasing or blocking afferent activity often results in stunted neuronal development and dendritic retraction. For example, in the visual system, visual deprivation from dark rearing decreases the length and number of branches of stellate neuron dendrites (Coleman and Riesen, 1968). Also, in the lateral geniculate nucleus, monocular deprivation can dramatically decrease soma size and dendritic morphology (Wiesel and Hubel, 1963; Guillery, 1973; Friedlander et al., 1982). Similarly, in the cerebellum, Purkinje cell dendrites are stunted in mutants in which the cerebellar granule cells fail to form synapses with Purkinje dendrites (Rakic and Sidman, 1973; Rakic, 1975; Sotelo, 1975). The resulting dendritic arbors are much smaller and less complex, and the number of dendritic spines is dramatically reduced (Mason et al., 1997). Finally, decreasing afferent activity by in vivo NMDA receptor blockade decreases dendritic growth and branching of motor neurons in the peripheral nervous system and of Purkinje cells in the cerebellum (Kalb, 1994; Vogel and Prittie, 1995). Remarkably, the effects of afferents in maintaining dendritic form are often spatially localized to the sites of their contacts with the postsynaptic dendrite. This is most clearly evident in a series of elegant experiments in which afferents to the ventral dendrites of neurons in the nucleus laminaris of the chick brainstem were cut. This elimination of excitatory input by deafferentation causes retraction of the ventral dendrites whereas the dorsal dendrites, which retain innervation, remain unchanged (Benes et al., 1977; Deitch and Rubel, 1984). The dendritic atrophy in response to loss of innervation occurs rapidly: within 1 h there is a significant decrease in dendritic length (Deitch and Rubel, 1984). These results are often interpreted as indicating a role for afferent activity in maintaining dendrites, but these afferents could instead contribute activity-independent trophic support. However, more physiological manipulations of activity, such as unilaterally plugging an ear, also result in changes in dendritic differentiation. In high-frequency regions of the nucleus laminaris, dendrites receiving input from the deprived ear are shorter than normal, whereas in low-frequency regions, dendrites of deprived neurons are longer than normal (Smith et al., 1983). Thus, dendritic structure is rapidly responsive to changes in afferent activity. Increasing afferent activity by raising either young or adult rats in enriched environments also has potent effects on dendritic arbors. In many cortical areas, exposure to an enriched environment can increase dendritic branching of pyramidal neurons (Holloway, 1966; Volkmar and Greenough, 1972; Greenough and Volkmar, 1973; Juraska, 1982). These results are intriguing and have been used to support the hypothesis that experience alters dendritic form dynamically in both the developing and the mature animal as it interacts with its environment. However, raising animals in enriched environments is likely to have complex effects on the nervous system, including nutritional and hormonal changes. Thus, the resulting changes in dendritic growth are not as directly interpretable as changes in dendritic growth caused by alterations in sensory activity. In addition to the large number of studies demonstrating a role for activity in regulating dendritic growth, there are also a number of studies that found no effect of activity in regulating dendritic growth, despite a strong dependence on afferent innervation (Goodman and Model, 1990; Dalva et al., 1994; Kossel et al., 1997; Drakew et al., 1999; Frotscher et al., 2000). Most of these studies relied on tetrodotoxin (TTX), which selectively blocks Na-channels, to block activity. Although TTX does block all Na-dependent action potentials, and therefore most neuronal activity, neurons will still spontaneously release and respond to glutamate in the presence of TTX. Indeed, there are several recent reports that glutamate released in the presence of TTX may regulate dendritic growth and spine formation (McAllister et al., 1996; Lin and Constantine-Paton, 1998; McKinney et al., 1999). A direct test of this possibility will be to examine dendritic growth in mice genetically engineered to lack neurotransmitter secretion at all synapses due to a deletion of Munc18-1 (Verhage et al., 2000). Verhage and colleagues report grossly normal brain development and synapse formation in these mice, but no quantitative analyses of dendritic growth have yet been performed. Recently, the role of specific forms of activity in inf luencing dendritic growth in vivo has been studied in an elegant series of experiments from Cline and colleagues. By imaging the dynamics of tectal neuron dendrites in vivo, dendritic structure was found to be plastic early in development and then much more stable as synapses form on these cells (Wu et al., 1999). NMDA receptor activation is required for normal dendritic elaboration in the tectum and acts to stabilize tectal dendrites (Rajan et al., 1999). Blockade of NMDA receptors early in development, when synapses are exclusively composed of NMDA receptors (Wu et al., 1996), causes loss of dendrites, while blocking AMPA receptors at this time has no effect (Rajan and Cline, 1998). Later in development, once AMPA receptors have been recruited to synapses, AMPA receptor blockade also results in loss of dendrites (Rajan and Cline, 1998). Blocking Activity Can also Elicit Paradoxical Increases in Dendritic Growth In some cases, rather than decreasing dendritic growth, blocking synaptic activity paradoxically increases dendritic growth. For example, monocular or binocular lid suture in young macaques dramatically increases growth of dendrites of stellate neurons in layer 4 (Lund et al., 1991). Similarly, blocking glutamate receptors or L-type calcium channels increases dendritic growth of pyramidal and nonpyramidal neurons in cultured slices of ferret visual cortex (McAllister et al., 1996; Baker et al., 1997). Blocking NMDA receptors in neonatal ferrets in vivo also increases dendritic branching and spine formation in neurons in the lateral geniculate nucleus (Rocha and Sur, 1995). Evidence that AMPA receptor activation can also limit dendritic growth comes from mutant mice expressing different alleles of the AMPA receptor GLUR-B subunit (Feldmeyer et al., 1999). The increased calcium inf lux through A MPA receptors in these mutants results in stunted dendritic growth of pyramidal neurons in the CA3 region of the hippocampus (Feldmeyer et al., 1999). In addition to a potent role for excitatory inputs, inhibitory inputs are also important in regulating dendritic growth. Early in development, at a time when GABA acts to depolarize neurons, elimination of inhibitory inputs to neurons in the lateral superior olive results in increased dendritic growth (Sanes et al., 1992). Thus, the effects of neuronal activity on dendritic form may be site- and context-dependent. These paradoxical effects of decreased activity in enhancing dendritic growth are poorly understood. Perhaps the simplest explanation for the widely differing effects of activity in these studies is that the cellular and molecular mechanisms of dendritic growth may differ between animal species and between brain regions. Alternatively, the direction of the effects of activity on dendritic growth may depend on the age of the neuron: very young neurons might react to decreased afferent activity with increased growth to search for active synaptic targets, while older neurons might simply retract their dendrites. There might also be differential effects of acute versus chronic activity blockade on dendritic growth. These differences could translate into particular intracellular calcium levels that are either conducive or prohibitive for dendritic growth. Clearly, the effects of neuronal activity on dendritic growth are complex. However, these complexities provide an opportunity to enhance our understanding of the precise cellular mechanisms that transduce the effects of activity into structural changes in the dendritic arbor. Specific Patterns of Afferent Activity also Regulate Dendritic Arborization The regulatory role of activity on dendritic differentiation is further evidenced by studies that suggest that the direction of growth of dendritic arbors is guided by a tendency to maximize contacts with inputs from functional sources, and more specifically, with inputs that have specific patterns of activity. In the visual system, the segregated pattern of afferent input to ocular dominance columns inf luences dendritic growth of neurons in the visual cortex (Kossel et al., 1995). Dendrites of neurons close to ocular dominance borders remain preferentially in one column and do not usually extend across borders (Katz and Constantine-Paton, 1988; Katz et al., 1989). Also, following visual deprivation, dendrites of layer 4 stellate neurons in the visual cortex show increased growth toward layer 3 as compared with dendrites in normally reared rats (Valverde, 1968; RuizMarcos and Valverde, 1970; Borges and Berry, 1976). In the auditory system, monaural deprivation results in decreased dendritic development toward inputs from the deprived side in the superior olivary nucleus (Feng and Rogowski, 1980). Finally, in the somatosensory system, neonatal damage to vibrissa row C in the mouse changes the orientation of corresponding row C dendrites in somatosensory cortex toward the remaining functional inputs in rows B and D (Harris and Woolsey, 1981). Specific patterns of activity may also guide selective pruning of dendritic arbors. For example, in the developing retina, ONand OFF-center retinal ganglion cells (RGCs) originally have overlapping dendrites. However, over time, their dendritic arbors stratify into different sublaminae of the inner plexiform layer (Wingate, 1996). Manipulations that block glutamate release onto ON-center RGCs prevent this stratification (Bodnarenko and Chalupa, 1993; Bisti et al., 1998). Dendrites of RGCs may also compete for afferent innervation, thereby adjusting the size of the dendritic arbor to the available space. For example, in the retina, ablation of RGCs causes neighboring RGC dendrites to expand into the cell-poor region, while addition of extra neurons causes dendritic arbors to shrink (Kirby and Chalupa, 1986; Leventhal et al., 1988; Perry and Maffei, 1988; Troilo et al., 1996). Activity Regulates the Dynamics of Dendritic Filopodia and Spines In addition to these dramatic effects on dendritic growth and branching, neuronal activity also regulates the number of dendritic filopodia on neurons in many areas of the nervous system. Although dendritic filopodia have generally been considered precursors of dendritic spines, recent studies suggest that they disappear before spine formation, that they may be a substrate for new branch formation, and that they may actively enhance synapse formation on developing dendrites (Dailey and Smith, Cerebral Cortex Oct 2000, V 10 N 10 965 1996; Fiala et al., 1998). Although signals that regulate spine formation are likely to be different from those that inf luence dendritic growth and arborization (Harris and Kater, 1994; Harris, 1999), signals regulating the formation of dendritic filopodia may overlap with those that regulate dendritic growth. Recently, several studies have been published that directly image changes in dendritic filopodial extension in response to electrical stimulation (Wong and Wong, 2000). As demonstrated by 2-photon imaging, local tetanic stimulation of pyramidal neurons in hippocampal slice cultures causes a localized, increased rate of filopodial extension that is completely prevented by NMDA receptor activation (Maletic-Savatic et al., 1999). In addition, endogenous activity has been shown to inf luence filopodial dynamics in the developing retina. Blocking glutamate receptors in the intact developing retina results in decreased filopodial dynamics of RGCs (Wong and Wong, 2000). However, this may be a phenomenon restricted to the retina as there is no reported change in spine dynamics in cortical, hippocampal or cerebellar slices in the absence of glutamatergic transmission (Dunaesky et al., 1999). Finally, focal electrical stimulation eliciting long-term potentiation (LTP) in chronic hippocampal slice cultures was found to stimulate rapid, local formation of new dendritic spines, perhaps as a structural substrate for LTP (Engert and Bonhoeffer, 1999). As a whole, these studies suggest that dendritic filopodial formation may be tightly and locally regulated by electrical activity from presynaptic axons. The Synaptotropic Hypothesis of Dendritic Growth The tendency of dendrites to grow toward sources of input suggests that formation of synaptic contacts may guide dendritic growth (Morest, 1969). In 1989, Vaughn proposed the synaptotropic hypothesis of dendritic branching that suggests that dendritic branches are formed at points of synaptic contact and that new dendritic branches are stabilized by synapses (Vaughn, 1989). Consistent with this hypothesis, dendritic growth of cultured hippocampal neurons is directly and locally regulated by glutamate; local application of glutamate to dendritic growth cones immediately stops growth, whereas blocking synaptic transmission stimulates dendrite outgrowth (Mattson et al., 1988a,b; Metzger et al., 1998). Perhaps most importantly, cultured hippocampal neurons form dendritic branches only in the presence of afferent innervation. Even on the same neuron, innervated dendrites are highly branched while non-innervated dendrites remain unbranched (Kossel et al., 1997). The synaptotropic hypothesis also predicts that the branches of dendrites that have synapses that are transitory or weakened, as in a model of synaptic competition, will retract (Vaughn, 1989). In many areas of the brain, there is a period of retraction of dendrites to form the adult pattern (Miller, 1988; Koester and O’Leary, 1992). A correlate of this theory is that dendritic patterning will be locally regulated by electrical activity at each synaptic contact. Recently, it has been shown that increases in synaptic activity stimulate new growth of dendritic spines and filopodia (Engert and Bonhoeffer, 1999; Maletic-Savatic et al., 1999). If these new filopodia form synapses, then this filopodial induction could represent a structural correlate of synaptic plasticity that is important for the establishment of connections not only during development, but also during learning and memory (Katz and Shatz, 1996). Extracellular Molecular Signals Regulate Dendritic Growth Despite our detailed knowledge of the morphological events in 966 Mechanisms of Dendrite Growth • McAllister dendritic development, the specific molecular signals involved in regulating dendritic growth are just beginning to be elucidated. This is a rapidly expanding field and new studies on dendritic growth are constantly emerging. Consistent with the idea that dendritic growth is regulated dynamically by afferent inner vation and synapse formation, many of the molecular signals that inf luence dendritic growth also regulate axon guidance and synapse formation, and their expression levels are modulated by synaptic activity. Neurotrophins The neurotrophins are attractive candidates for molecular signals that regulate dendritic growth. The neurotrophins include at least four structurally and functionally related proteins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4. These factors exert their effects by binding to high-affinity tyrosine kinase receptors, the Trk receptors, and to a low-affinity receptor called p75 (McAllister et al., 1999). Both the neurotrophins and their receptors are most highly expressed in the developing nervous system during times of active neuronal growth and differentiation (McAllister et al., 1999). In addition, all of the neurotrophins have dramatic effects on axon outgrowth during development of both the peripheral and central nervous systems (Snider, 1994). Neurotrophins were first demonstrated to regulate dendritic growth in the peripheral nervous system in an elegant series of experiments by Snider and colleagues (Purves et al., 1988; Snider, 1988; Ruit et al., 1990; Ruit and Snider, 1991). Their experiments consisted of systemic treatment of neonatal and adult rats with NGF for 1–2 weeks. This treatment causes a dramatic expansion of dendritic arbors of sympathetic ganglion cells (Snider, 1988; Ruit et al., 1990). Conversely, injections of NGF antiserum in adult rats decrease the dendritic length of sympathetic neurons. In the CNS, neurotrophins regulate dendritic growth of pyramidal neurons in the developing neocortex (McAllister et al., 1995; Baker et al., 1998). Each of the four neurotrophins, when applied to organotypic cortical slices for only 36 h, rapidly increases the length and complexity of dendrites of cortical pyramidal neurons (McAllister et al., 1995). Neurons in each cortical layer respond to subsets of neurotrophins with distinct effects on apical and basal dendrites and, within a single cortical layer, each neurotrophin elicits a unique pattern of dendritic changes (McA llister et al., 1995). Furthermore, pyramidal neurons that overexpress BDNF sprout more basal dendrites and retract their existing dendritic spines (Horch et al., 1999). The dendrites of these cells are much more plastic than nontransfected control dendrites, suggesting that BDNF induces structural instability in both dendrites and spines (Horch et al., 1999). The spectrum of neurotrophin effects and the laminar specificity of these actions imply that neurotrophins act instructively to regulate development of specific patterns of dendritic arborizations in neocortex. Endogenous neurotrophins also clearly exert a powerful inf luence over the precise form of the dendritic arbors of pyramidal neurons in the developing visual cortex (McAllister et al., 1997). Using Trk receptor bodies to remove endogenous neurotrophins, we demonstrated that endogenous neurotrophins not only enhance dendritic growth but can also limit growth and even cause dendritic retraction, depending on the layer-specific location of the neurons examined. Moreover, BDNF and NT-3 have opposing roles in regulating dendritic growth; they interact in a ‘push–pull’ fashion as a signaling system to regulate dendritic arborization. These antagonistic roles for BDNF and NT-3 provide a potential mechanism by which dendritic growth and dendritic retraction can be dynamically and locally regulated by intercellular interactions. In addition to their effects in the developing visual cortex, neurotrophins also inf luence dendritic growth of neurons in the developing retina and cerebellum. Local addition of BDNF in vivo reduces the complexity of dendritic arbors of retinal ganglion cells, while neutralization of endogenous BDNF levels with locally applied function-blocking antibodies increases dendritic arbor complexity (Lom and Cohen-Cory, 1999). In the developing cerebellum, BDNF is necessary for the proper development of Purkinje cell dendrites; these dendritic arbors are stunted in BDNF–/– mice (Segal et al., 1995; Schwartz et al., 1997). However, altering BDNF levels postnatally does not inf luence dendritic arborization of Purkinje cells but does dramatically increase the number of dendritic spines (Morrison and Mason, 1998; Shimada et al., 1998). Recently, neurotrophins have been the focus of much attention as potential mediators of activity-dependent structural plasticity (McAllister et al., 1999). In support of this model, we (McAllister et al., 1996) have recently demonstrated that neurotrophins effect preferentially active neurons. Inhibition of spontaneous electrical activity, synaptic transmission or L-type calcium channels each completely prevents the dramatic increase in dendritic arborizations elicited by exogenous BDNF. Thus, neurons must be active in order to respond to the growth-promoting effects of BDNF (McAllister et al., 1996). This requirement for conjoint neurotrophin signaling and synaptic activity provides a mechanism for selectively enhancing the growth of dendrites receiving inputs from active neurons in the developing nervous system. Semaphorins Semaphorin 3A (Sema3A) is another clear example of an axon guidance molecule that also affects dendritic growth. Sema3A acts as a chemorepellant for cortical axons (Polleux et al., 1998) and as a chemoattractant for apical dendrites of cortical neurons (Polleux et al., 2000). This diffusible signal is thought to be secreted at high levels from cells in cortical layer 1. Apical dendrites of pyramidal neurons normally extend directly toward layer 1 in the cerebral cortex, but can be induced to extend in any direction within the cortex toward a source of Sema3A (Polleux et al., 2000). This chemoattractant effect is mediated by the Sema3A receptor neuropilin-1, and by a selective distribution of soluble guanylate cyclase in the apical dendrite (Polleux et al., 2000). Cpg15 Cpg15, a gene isolated from a screen for activity-regulated genes, is another compelling candidate for a molecular signal that inf luences dendritic growth and plasticity (Nedivi et al., 1998). CPG15 is predicted, by sequence analysis, to be a secreted protein that is membrane-bound by a GPI linkage. During development, CPG15 is expressed in areas undergoing afferent innervation, dendritic elaboration and synapse formation (Corriveau et al., 1999). When transfected into the Xenopus tectum in vivo, CPG15 enhances dendritic growth exclusively in projection neurons. CPG15 acts to enhance dendrite growth of neighboring neurons through an intercellular mechanism requiring its GPI link (Nedivi et al., 1998). As Nedivi and colleagues emphasize (Nedivi et al., 1998), because it is membrane- bound, CPG15 is in a unique position to exert precise spatial specificity in its regulation of dendritic growth in response to synaptic activity. Ephrins The ephrins are a large family of signaling molecules recently implicated in the topographic patterning of axon guidance in the visual system (Flanagan and Vanderhaeghen, 1998; O’Leary et al., 1999). In addition to effects on axon guidance, ephrins may also inf luence the growth of dendrites of pyramidal neurons in the developing visual cortex. Transfection of pyramidal neurons in cultured ferret visual cortical slices with the receptor EphA3 decreases dendritic branching of both basal and apical dendrites of transfected neurons (Butler et al., 1999). These studies provide further support for the idea that the same molecular signal can act both pre- and postsynaptically to regulate neuronal form. Osteogenic Proteins Several members of the bone morphogenetic protein (BMP) family, which are members of the transforming growth factorbeta superfamily, also inf luence dendritic growth. Osteogenic protein-1 (OP-1), BMP-6, BMP-2 and Drosophila 60A protein induce the growth of dendrites in rat sympathetic ganglion neurons, accompanied by increased expression of the microtubule-associated protein, MAP2 (Guo et al., 1998). This induction by OP-1 requires NGF as a cofactor (Lein et al., 1995). Recently, OP-1 was demonstrated to stimulate dendritic growth of cultured cortical neurons (Le Roux et al., 1999). These studies suggest that several members of the BMP family can inf luence dendritic growth, possibly through induction of cytoskeletal proteins (Guo et al., 1998). Notch Based on its ability to regulate axon outgrowth, a number of laboratories have begun to focus on Notch signaling as a potential molecular regulator of dendritic growth (Franklin et al., 1999). Notch is a cell-surface protein that functions as a receptor for its ligand, Delta, and is involved in cell fate decisions during early development (Redmond et al., 2000). As Notch continues to be expressed at high levels in neurons during differentiation, it has been hypothesized that it might regulate neurite outgrowth. Young cortical neurons with low Notch activity readily extend dendrites; up-regulation of Notch decreases dendritic growth in these cells (Berezovska et al., 1999; Sestan et al., 1999; Redmond et al., 2000). Similarly, more mature neurons with high Notch activity exhibit little dendritic growth, and down-regulation of Notch in these cells promotes dendritic growth (Franklin et al., 1999; Sestan et al., 1999; Redmond et al., 2000). Molecular perturbation experiments of Notch1 suggest that Notch1 signaling in cortical neurons promotes dendritic branching but inhibits dendritic growth (Redmond et al., 2000). Thus, the formation of interneuronal contacts may up-regulate Notch activity and thereby restrict subsequent dendritic growth. Cell Adhesion Molecules Recent studies also suggest a role for cell adhesion molecules in regulating dendrite growth in the developing cortex. Homophilic L1 binding between neurons activates signal transduction cascades necessary for axon outgrowth in culture (Schachner, 1991). In addition to striking defects in axon growth, L1 knockout mice also exhibit defects in the growth of apical dendrites of pyramidal neurons in motor, visual and somatosensory cortices Cerebral Cortex Oct 2000, V 10 N 10 967 (Demyanenko et al., 1999). Similarly, mice lacking the cell adhesion molecule, contactin, show decreased dendritic growth of granule and Golgi cells, but not Purkinje cells, in the developing cerebellum (Berglund et al., 1999). A lthough these studies are intriguing, because of the transgenic approach, it is difficult to determine whether cell adhesion molecules act directly on dendritic growth or whether they inf luence dendritic growth indirectly by directly inf luencing axon guidance. Future experiments using single cell knockouts in a normal tissue background may clarify these issues. Glia Based on the fact that glial cells in the brain secrete many of the factors known to regulate dendritic growth, it is not surprising that glia are important for dendritic growth and arborization. Glial cells enhance dendritic growth of neurons from both the peripheral and the central nervous systems in culture; in the absence of glia, neurons generally exhibit stunted dendritic arbors that are much less branched than in the presence of glia (Tropea et al., 1988). Furthermore, astrocytes from different areas of the brain differ in their ability to maintain primary dendrites of cultured cortical neurons (LeRoux and Reh, 1995a). Although immature astrocytes promote both axonal and dendritic growth, mature astrocytes selectively promote dendritic growth, implying that there are growth signals that act exclusively on dendrites (LeRoux and Reh, 1995b). Hormones For many years, it has been known that hormones, including thyroid hormone, estrogen and glucocorticoids, also inf luence dendritic growth (Gould et al., 1991). Hypothyroid rats have reduced dendritic and axonal arbors, while hyperthyroid rats exhibit enhanced dendritic arborization. For example, cerebellar Purkinje cells have fewer dendritic branches in hypothyroid rats (Nicholson and Altman, 1972). Thyroid hormone treatment of neonatal rats results in an increase in elaboration of dendrites of pyramidal neurons in hippocampal area CA3 (Gould et al., 1990b); treatment of adult rats has no effect on the dendritic arbor but instead dramatically decreases the number of dendritic spines (Gould et al., 1990a). Gonadal hormones also regulate dendritic growth. In slice cultures of the hypothalamus and preoptic area, estradiol treatment markedly increases dendritic outgrowth (Toran-Allerand et al., 1983). Although the results are complex, in general, estrogen increases dendritic spine density while progesterone dramatically decreases it (Woolley and McEwen, 1993). Finally, exposure to high levels of glucocorticoids specifically decreases apical dendritic length and complexity of pyramidal neurons in the CA3 region of the hippocampus (Woolley et al., 1990). These studies suggest that hormones modulate dendritic form in both the developing and adult nervous systems, and may thus permit the state of the animal to inf luence neuronal connectivity. Intracellular Molecules Regulate Dendritic Growth Recently, a number of laboratories have started to study the intracellular mechanisms that regulate dendritic growth and arborization. Although this field of study is in its infancy, several compelling intracellular molecular mediators of dendritic growth have been identified. Many of the intracellular signals that mediate axonal growth also affect the growth of dendrites; however, there are a number of interesting differences. Importantly, a majority of these signals are directly regulated 968 Mechanisms of Dendrite Growth • McAllister by synaptic activity, supporting the hypothesis that dendrites are stabilized by synapses and rapidly modified by synaptic activity. Calcium/Calmodulin-dependent Protein Kinase II (CamKII) CamKII has been proposed to translate calcium inf lux through postsynaptic receptors into long-lasting structural changes in neurons. Consistent with this hypothesis, altering CamKII levels in the Xenopus tectum in vivo alters the stability of dendritic arbors (Zou and Cline, 1999). Transfection of tectal neurons with constitutively active CamKII early in development stabilizes dendritic arbors by slowing dendritic growth to adult levels (Wu and Cline, 1998). Similarly, CamKII inhibition in mature neurons increases the rate of dendritic growth (Wu and Cline, 1998; Zou and Cline, 1999). These results suggest that activated CamKII acts as a ‘STOP’ growth signal and thus might be the signal that transforms dynamic, immature synapses into more stable, mature synapses. Molecular Motors and MAPs Dendritic growth is crucially dependent on targeted changes in the cytoskeleton. The cytoskeleton of dendrites is composed of microfilaments and microtubules. Both of these proteins are dynamic polymers of actin and tubulin, respectively, and the balance between polymerization and depolymerization is tightly controlled by the cell (Kirschner and Mitchison, 1986). This equilibrium can be rapidly shifted in response to a variety of physiological signals. Microtubules start polymerizing at a nucleating center often located in the cell body beneath a dendrite (Kirshner and Mitchison, 1986). These microtubules are transported from the cell body into the developing dendrite using a motor protein called CHO1/MKLP1 (Sharp et al., 1997). During rapid growth, microtubules are dynamically unstable but can become much more stable if the growing end of the polymer is capped by microtubule-associated proteins (MAPs); the most prominent MAP located primarily in dendrites is MAP2 (Matus, 1988). Interestingly, MAP2 is a substrate for both the cA MPdependent and the Ca2+/calmodulin-dependent protein kinases (Mitchison and Kirshner, 1988). Phosphorylation of these MAPs decreases their ability to promote polymerization, thereby increasing dendritic instability. Thus, MAPs are probably crucial to determining dendritic form by regulating the balance between unstable and stable forms of microtubules (Matus, 1988). GTPases On a faster time-scale, dendritic changes involve rapid dynamics of dendritic filopodia that must involve changes in actin (Smith, 1999). Many laboratories have started to focus on the Rho family of small GTPases, including Rho, Rac and Cdc42, as they are known to be powerful intracellular regulators of signaling pathways to the actin cytoskeleton (Luo et al., 1997). These GTPases regulate dendritic growth and complexity in several areas of the brain (Luo et al., 1994, 1996; Threadgill et al., 1997; Ruchhoeft et al., 1999; Li et al., 2000). In cultured cortical neurons, blocking Rac or Cdc42 by expressing dominant negative mutants reduces the number of primary dendrites; expressing constitutively active forms of Rho, Rac or Cdc42 increases primary cortical dendrites in culture (Threadgill et al., 1997). The roles of these GTPases in dendritic growth in vivo are quite complex. Previous studies of Rho-family GTPases have demonstrated that their function is extremely context-dependent. Expression of mutant forms of RhoA, Rac1 and Cdc42 in vivo in developing Xenopus retinal ganglion cells indicates that each of these proteins has distinct effects on dendritic growth and branching. Increasing RhoA activity causes a dramatic retraction of almost all dendrites while increasing Rac1 activity enhances dendritic growth (Ruchhoeft et al., 1999). Consistent with these results, increasing Rac and Cdc42 activity in vivo in Xenopus tectal neurons increases dendritic branching dynamics (Li et al., 2000). However, increasing RhoA activity decreases dendritic branch extension and decreasing RhoA activity increases it (Li et al., 2000). Most importantly, RhoA mediates the increase in dendritic growth caused by NMDA receptor activation (Li et al., 2000). All of these studies suggest that these small GTPases act together to regulate dendrite growth dynamically. These small GTPases are in a perfect position to mediate the rapid effects of synaptic activity and neurotrophin activation in altering dendritic morphology. Novel Candidate Genes that May Regulate Dendritic Form One of the most promising studies of the molecular mechanisms of dendritic growth is a recent genetic screen to identify genes that control specific aspects of dendrite growth and patterning in Drosophila (Gao et al., 1999). This screen has identified 14 genes that inf luence the growth of dendrites of Drosophila dorsal sensory neurons. The transcription factor Prospero and the small GTPase Dcdc42 regulate dendritic outgrowth. Additional genes identified in this screen are: (i) kakapo, a large cytoskeletal protein involved in axonal outgrowth; (ii) f lamingo, a seven-transmembrane protein with cadherin-like repeats; (iii) enabled, a substrate for the tyrosine kinase Abl that is involved in actin polymerization; and (iv) nine potentially novel genes (Gao et al., 1999). Future studies elucidating the function of these proteins in regulating dendritic growth should provide significant insight into the molecular mechanisms of dendrite development. Concluding Remarks Dendritic mRNAs The protein synthesis and post-translational modification of proteins required for the growth of dendrites may be facilitated by polyribosomes located at the base of dendritic spines (Steward et al., 1988; Eberwine, 1999). Polyribosome clusters are sites of protein synthesis. The location of polyribosomes at the base of dendritic spines may enable protein synthesis to be regulated by activity at individual synapses (Steward and Levy, 1982; Steward, 1995; Gardiol et al., 1999). As protein synthesis may be required for long-term synaptic changes, such as LTP (Nguyen et al., 1994; Huang, 1999), dendritic mRNA and local protein synthesis at spines could facilitate local production of proteins necessary for activity-dependent synaptic strengthening and spine formation. Immediate early genes (IEGs) are also likely to be involved in the fast, activity-dependent dendritic dynamics described above. These genes are rapidly and transiently expressed in response to synaptic activity and growth factors (Lanahan and Worley, 1998). A number of IEGs have recently been identified in a screen for activity-dependent genes and several of these are preferentially expressed in dendrites. One of the first IEGs implicated in activity- and growth-factor-dependent dendritic plasticity was isolated in 1995 (Lyford et al., 1995). This gene, named Arc for activity regulated cytoskeleton-associated protein, is rapidly induced by both neuronal activity and growth factors, and is enriched in neuronal dendrites. It has a homologous region to alpha-spectrin, coprecipitates with F-actin and colocalizes with the actin cytoskeletal matrix just beneath the dendritic plasma membrane. Arc is rapidly regulated by physiological synaptic activity. Arc mRNA is decreased in areas of visual cortex receiving decreased inputs due to monocular TTX retinal injections; it appears to be exclusively targeted to dendrites and thus is in an optimal location to modify dendritic structure by interacting with the cytoskeleton in response to local changes in activity or growth factor levels (Lyford et al., 1995). Another IEG that is rapidly induced in the hippocampus and cerebral cortex by physiological activity is called Narp, for neuronal activityregulated pentraxin (Tsui et al., 1996). This protein is secreted, clusters AMPA receptors at synaptic sites and stimulates dendritic growth from cultured cortical neurons (Tsui et al., 1996; O’Brien et al., 1999). Thus, Narp may be one of the molecular signals that regulates concurrent dendritic growth and synapse formation. As dendrites are the sites of most synapses on a neuron, dendritic growth and arborization are clearly crucial for proper development of the nervous system. As discussed above, dendritic growth is potently regulated by environmental signals, including synaptic activity. Research into the cellular and molecular mechanisms of dendrite growth is just beginning to reveal clues as to how local, afferent synaptic stimulation might inf luence dendritic growth, branching and spine formation. In light of the rapid rate of advances in this field, it is reasonable to predict that our understanding of the signals that regulate dendritic growth will advance quickly over the next few years. Currently, the most compelling hypothesis of dendritic growth is the synaptotropic theory described by Vaughn (Vaughn, 1989). This hypothesis predicts that dendritic branches are stabilized and stimulated to grow by synaptic contacts. The overwhelming evidence that afferent innervation is necessary for proper formation of dendrites is consistent with this theory. Furthermore, direct support for the synaptotropic theory comes from real-time 2-photon imaging of local extension of dendritic filopodia in response to local synaptic stimulation (MaleticSavatic et al., 1999). This exciting result suggests that levels of activity at individual synapses can locally modify the structure of the postsynaptic neuron. However, it is crucial to follow the fate of these locally induced filopodia over time to see if larger-scale dendritic growth, such as branch formation, is induced by local synaptic activation, as proposed in the synaptotropic theory. The common message from the majority of papers in the field of dendrite development is that dendritic growth is dynamic and closely inf luenced by synapse formation and function. In fact, most of the extra- and intracellular signals that inf luence dendritic growth also alter synapse formation and axon guidance. In light of this intimate relationship between dendritic growth and synaptogenesis, it seems obvious that the molecules involved in one process will necessarily inf luence the other. However, historically and for practical reasons, scientists have artificially separated the signals that regulate axon growth from those that regulate dendritic elaboration and synapse formation. The fact that these processes are interconnected might help to explain why the number of molecular signals that inf luence dendritic arborization is so large (and is sure to grow much larger in the near future). Activity-dependent dendritic growth implies that dendritic arborization is not only determined by the intracellular components of the dendrite but is also inf luenced by Cerebral Cortex Oct 2000, V 10 N 10 969 both the molecular components of the synapse and the axon, and by the signals that inf luence synaptic stability. This large number of molecular players acting in concert may enable dendrites to be exquisitely responsive to changes in local signals from connected neurons — a capability necessary for activitydependent development and also perhaps for adult plasticity. One implication of the synaptotropic theory is that activity/ experience-dependent processes known to guide changes in neuronal connectivity during development may not only act on axons but may also strongly inf luence dendritic form. If specific patterns of synaptic activity act to strengthen or weaken a synapse, then it makes sense that both the axon and the dendrite will undergo subsequent structural changes. In order to understand the cellular consequences of these activity-dependent changes, the molecular events in synapse formation and the structural correlates of synaptic strengthening or weakening must be elucidated. Surprisingly, we know very little about the cellular and molecular mechanisms of synapse formation. As synaptogenesis and dendritic growth are intimately connected, results from experiments in both fields should converge to provide a clearer understanding of the cellular and molecular mechanisms of dendritic growth. 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