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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.
Notes
I wish to thank Amy Butler and Martin Usrey for their insightful
comments on this manuscript.
Address correspondence to A. Kimberley McAllister, Center for
Neuroscience, UC Davis, 1544 Newton Court, Davis, CA 95616, USA.
Email: [email protected].
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