REVIEW ARTICLE
published: 28 December 2012
doi: 10.3389/fncel.2012.00061
Molecular mechanisms of dendrite morphogenesis
Jyothi Arikkath*
Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
Edited by:
Eran Meshorer, The Hebrew
University of Jerusalem, Israel
Reviewed by:
Marco Martina, Northwestern
University, USA
Daniel N. Cox, George Mason
University, USA
*Correspondence:
Jyothi Arikkath, Developmental
Neuroscience, Munroe-Meyer
Institute, University of Nebraska
Medical Center, Omaha,
NE 68198, USA.
e-mail: Jyothi.arikkath@unmc.edu
Dendrites are key integrators of synaptic information in neurons and play vital roles in
neuronal plasticity. Hence, it is necessary that dendrite arborization is precisely controlled
and coordinated with synaptic activity to ensure appropriate functional neural network
integrity. In the past several years, it has become increasingly clear that several cell
intrinsic and extrinsic mechanisms contribute to dendritic arborization. In this review, we
will discuss some of the molecular mechanisms that regulate dendrite morphogenesis,
particularly in cortical and hippocampal pyramidal neurons and some of the implications
of aberrant dendritic morphology for human disease. Finally, we will discuss the current
challenges and future directions in the ﬁeld.
Keywords: dendrite, molecular mechanims, arborization, aberrant dendritic morphology, plasticity and learning
INTRODUCTION
Neurons are highly specialized and polarized cells that have morphologically
distinct regions optimized for their functional roles.
Most neurons have several dendrites that represent the information
input centers of the neuron and single axons that represent
the information output centers. The majority of our understandings
of the cellular and molecular mechanisms that control
neuronal morphology have come from studies on the pyramidal
neurons, which represent the vast majority of excitatory neurons
in the hippocampus and cortex. In this review, we will
focus on some of the more recent studies that have provided
critical insights into the molecular and cellular mechanisms that
control neuronal morphology, with particular reference to dendrites
of pyramidal neurons in the hippocampus and cortex. In
addition, we will review the consequences of aberrations in dendritic
arborization in disease. Finally, we will discuss the current
challenges in the ﬁeld.
DENDRITIC STRUCTURE AND FUNCTION
Axons harbor presynaptic terminals that contain neurotransmitter
bearing vesicles. The presence of voltage gated sodium
channels allows the propagation of action potentials along the
length of the axon to the presynaptic terminals, thus promoting
neurotransmitter release. Dendrites bear synapses, both excitatory
and inhibitory (Figure 1). Synapses represent major sites of
information input into neurons.
The structure and arborization of dendrites has a profound
impact on the processing of neuronal information. Most of
the pyramidal neurons in the cortex and hippocampus have a
characteristic pyramidal morphology with distinct large apical
and shorter basolateral dendrites that originate from the apex
and base of the soma respectively, each with multiple branches.
Cortical pyramidal neurons are organized into six layers and
neurons from each layer have characteristic dendrite branching
patterns, coincident with their functional roles (Spruston,
2008). Synapses are the major sites of information input into
neurons. The pattern of dendritic arborization is critical because
it determines the synaptic input ﬁeld of the dendrite. Distinct
dendritic regions receive synaptic input from different sources.
For example, the CA1 neurons in the hippocampus receive their
input at the apical tuft dendrites from the entorhinal cortex,
while the basal dendrites receive their input from the CA3 neurons.
In addition to functional synapses, dendrites also harbor a
variety of receptors, channels (Lujan et al., 2009) and signaling
molecules, including extrasynaptic NMDA (Petralia et al., 2010;
Papouin et al., 2012) and GABA (Kasugai et al., 2010) receptors,
that regulate various aspects of neuronal function (Ratnayaka
et al., 2011), including cell death. Emerging evidence suggests
that these non-synaptic receptors may also play key roles in the
transmission of neuronal information (Ratnayaka et al., 2011). In
contrast to the classical view, it is now clear that dendrites do not
merely function in passive signal propagation but play key active
roles in local signal computation (Larkum et al., 2009; Branco
et al., 2010; Branco and Hausser, 2011; Emoto, 2012; Kim et al.,
2012). The integration of presynaptic and postsynaptic events is
strongly inﬂuenced by their location along the dendritic arbor.
Postsynaptic elements at distal synapses have the highest gain
for integration, while presynaptic elements located at the distal
end have the least gain (de Jong et al., 2012), thus the length
of the dendritic arbor is critical for signal integration. Dendritic
functional roles are also critical in the storage of long-term memory
(Govindarajan et al., 2011). Inhibitory interneurons form
the other major type of neurons in the cortex and hippocampus
(Mendez and Bacci, 2011) and are not as homogeneous as
the pyramidal neurons. Inhibitory neurons can be further classiﬁed
into various subclasses. Inhibitory interneurons also have
extensive dendritic arbors which have integral roles in neuronal
computation (Goldberg and Yuste, 2005; Camire et al., 2012),
however most of them do not harbor spines or have relatively
low spine densities. Thus mechanisms that regulate the initiation,
formation and maintenance of dendritic arbors can have a
profound inﬂuence on the formation and maintenance of neural
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CELLULAR NEUROSCIENCE
Arikkath Molecular mechanisms of dendrite morphogenesis
FIGURE 1 | Synaptic terminals on dendrites and schematic of
excitatory and inhibitory synapses: rat hippocampal neurons in
culture (DIV 17) transfected with GFP (green) and immunostained
with markers that label presynaptic terminals of either excitatory
(top, red—vGlut1) or inhibitory (bottom, red—GAD65) synapses.
Note that the excitatory synapses predominantly form on spine heads,
while the inhibitory synapses are predominantly localized in the
dendritic shaft. The presynaptic terminals contain neurotransmitter
loaded vesicles, while the postsynaptic region harbors neurotransmitter
receptors.
circuits and consequently higher order brain functions, including
learning and memory.
DEVELOPMENT OF DENDRITIC POLARITY
During development of the cortex and hippocampus, neurons are
speciﬁed, exit the cell cycle and undergo migration that eventually
allows them to reach their speciﬁed destination and form connections
with other neurons (Marin et al., 2010). In vivo, most
of these neurons undergo polarization during migration eventually
leading to a highly polarized neuron with extensive axonal
arbors and dendritic trees. Axons and dendrites are structurally
and functionally distinct and these distinctions are maintained
over the lifetime of the neuron. One of the central challenges
in neurobiology has been to determine the molecular mechanisms
that control the speciﬁcations of the axon vs. the dendrite.
Over the last several years, it has become apparent that several
extrinsic and intrinsic factors cooperate to determine the initiation
of neuronal polarity. While several molecular effectors that
control the speciﬁcation of axons, including PI3-kinase, PTEN,
GSK3β, the Par family of proteins and the SAD kinases (Barnes
et al., 2007; Barnes and Polleux, 2009; Shelly et al., 2011) have
been characterized, much less is known about how dendrite speciﬁcation
is achieved. Moreover, dendrites are not homogeneous
structures and it is unclear what the extrinsic and intrinsic cues
are that control dendritic polarity to allow the initiation, development
and maintenance of apical and basolateral and other
lateral dendrites. Given the roles of molecular effectors, local protein
degradation, cytoskeletal dynamics, and molecular motors
in the speciﬁcation of axons (de Anda et al., 2005), it is likely
that similar cues specialized for dendrites exist and remain to
be identiﬁed and characterized. Interestingly, a subset of neuronal
storage disorders with increased levels of GM2 ganglioside
result in the reinitiation of ectopic dendrites that form connections
on mature neurons in the cortex (Siegel et al., 2002),
suggesting that molecular cues exist that control dendrite initiation
separately from axon initiation and dysregulation of such
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Arikkath Molecular mechanisms of dendrite morphogenesis
mechanisms could have pathological consequences (Cox and
Cachon-Gonzalez, 2012).
DENDRITIC SYNAPSES
In the hippocampus and cortex, the majority of excitatory
synapses are formed on spines while inhibitory synapses are
predominantly formed on the cell bodies and dendritic shafts.
Spines are small protrusions that arise along the dendritic shaft.
Structurally, these have a long thin neck and a head that bears
the excitatory synapse (Figure 1), but can have varied morphology
(Bourne and Harris, 2008). Postsynaptic synapses bear the
synaptic machinery that can respond to neurotransmitters and
convey information. Spines and synapses are the major sites of
information input into the neurons. More importantly, they are
the major sites of dendritic plasticity (Matsuo et al., 2008; Harnett
et al., 2012; Sanders et al., 2012) and considerable effort has been
and is being directed toward deﬁning the molecular components
of these structures and understanding their contribution to plasticity
(Lai et al., 2012) and higher order brain functions, including
learning and memory (Vanleeuwen and Penzes, 2012). Moreover,
aberrations in synaptic structure and function are observed in a
variety of neurodevelopmental, neuropsychiatric, and neurodegenerative
disorders (Penzes et al., 2011; Yu and Lu, 2012). We
refer the readers to other excellent reviews on the roles of synapses
in plasticity (Bosch and Hayashi, 2012; Murakoshi and Yasuda,
2012; Okabe, 2012) and disease (Pavlowsky et al., 2012; Verpelli
and Sala, 2012).
MOLECULAR CONTROL OF DENDRITE ARBORIZATION
The establishment of the dendritic arbor involves dendrite
extension, addition, elongation, retraction, and pruning (Jan
and Jan, 2010; Emoto, 2012). These processes are inﬂuenced
by synaptic activity. In the adult, the dendritic arbor is
mostly stabilized and is only induced to undergo remodeling
under pathological conditions (Wu et al., 1999; McAllister,
2000).
Molecular mechanisms, both extrinsic and intrinsic, exist that
allow for exquisite temporal and spatial control of arborization
to ensure that the extensive dendritic arbor is correctly generated
and maintained during the lifetime of the organism. Moreover,
the functional roles of these molecules are intertwined and regulated
to allow for tight control over dendrite extension and
arborization.
In this review, we discuss the various classes of molecules that
control dendritic arborization in hippocampal and cortical neurons
with a few more recently identiﬁed examples from each
class. While some of these mechanisms and pathways have also
been implicated in dendrite morphogenesis in other types of neurons,
discussing other types of neurons is beyond the scope of
this review and we refer the readers to other excellent reviews
(Jan and Jan, 2010; de la Torre-Ubieta and Bonni, 2011) on these
topics.
Several classes of molecules participate in ensuring correct
dendritic architecture. These include secreted molecules, cell
surface receptors, cell adhesion molecules, postsynaptic density
proteins, signaling molecules, regulators of the actin cytoskeleton,
molecules that control Golgi trafﬁcking, calcium signaling
proteins, and transcription factors. Table 1 while several of these
proteins play important functional roles outside central neurons,
it is becoming increasingly appreciated that they control multiple
aspects of neuronal morphology, including dendritic branching
(Figures 2 and 3).
SECRETED FACTORS, CELL SURFACE RECEPTORS, AND CELL
ADHESION MOLECULES
Secreted factors can exert both paracrine and autocrine regulatory
effects on dendritic outgrowth and extension. Receptors and
cell adhesion molecules can participate in transducing external
stimuli into intracellular signaling cascades and thus inﬂuence
dendritic growth and branching.
BRAIN-DERIVED NEUROTROPHIC FACTOR
Neurotrophins are neurotrophic factors that play key roles in dendritic
growth and branching. Four members of the family include
nerve growth factor (NGF), brain derived neurotrophic factor
(BDNF) and neurotrophins 3 and 4 (NT-3 and NT-4). These factors
exert their effects through binding the TrK family of receptors
and the p75 neurotrophin receptor (p75NTR). Of these, BDNF is
the most widely studied and the most critical factor regulating
dendrite outgrowth and branching. Several studies have shown
that BDNF application increases dendrite number in pyramidal
neurons (McAllister et al., 1995; Horch and Katz, 2002), and
these increases in dendrite branching act in a distance-dependent
manner (Horch and Katz, 2002). Different isoforms of TrkB
receptors show different effects on dendrite branching. Full length
TrkB activation results in increased proximal dendrite numbers,
whereas truncated T1 promotes net elongation of dendrites when
overexpressed in cultured neurons (Yacoubian and Lo, 2000).
BDNF binds to the TrkB isoforms and activates various signaling
pathways, such as the Ras/MAPK cascade, PI3 kinase/Akt
pathway, and IP3-dependent calcium release. Thus, they promote
transcriptional changes for proteins that are involved in cell survival,
death, cytoskeletal changes, and neurite outgrowth (Chao,
2003; Segal, 2003). Recent studies show that distinct 5 UTR BDNF
transcripts differentially shape dendritic arbor in an area-speciﬁc
manner by selective activation of TrkB receptors (Baj et al.,
2011) suggesting that distinct mechanisms are involved in shaping
dendrite complexity.
REELIN
Reelin is a large, secreted extracellular matrix glycoprotein,
secreted by Cajal-Retzius cells during early cortical development.
Reelin is also expressed by interneurons through life (Liu et al.,
2001). While the role of Reelin in the migration of cortical
neurons has been well established, it is now clear that Reelin regulates
multiple aspects of neuronal development and maintenance,
including dendrite extension. Loss of Reelin leads to reduction
in dendrite growth and this effect of Reelin is mediated by signaling
through the very low density lipoprotein receptor and
the apolipoprotein E receptor 2 (D’Arcangelo, 2006). Conversely,
addition of reelin increases dendritic growth of hippocampal neurons
(Niu et al., 2004) and induces MAP1B phosphorylation via
activation of GSK3β (Lambert de Rouvroit and Gofﬁnet, 2001;
Gonzalez-Billault et al., 2005).
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Arikkath Molecular mechanisms of dendrite morphogenesis
Table 1 | Summary of molecules regulating dendritic morphogenesis.
Factor/molecule Functional role Role in dendrite Components References
morphogenesis of pathway
SECRETED FACTORS, CELL SURFACE RECEPTORS, AND CELL ADHESION MOLECULES
BDNF Neurotrophic factor Increases dendrite branching Cypin, MAPK, CREB Yacoubian and Lo,
2000; Horch and Katz,
2002; Baj et al., 2011
Reelin Extracellular matrix glycoprotein Increases dendritic growth VLDL receptor, apo E
receptor 2, MAP1B, GSK313
Lambert de Rouvroit
and Gofﬁnet, 2001;
Niu et al., 2004;
Gonzalez-Billault et al.,
2005; D’Arcangelo,
2006
Wnt family Secreted glycoproteins Promotes dendrite complexity Frizzled, disheveled, Rac,
Jnk, Par1b/MARK2
Rosso et al., 2005;
Terabayashi et al.,
2007
Ephrins and Eph
receptors
Receptor tyrosine kinases and
their ligands
Promotes dendrite arborization KIF5, GRIP1 Klein, 2009
Semaphorins Secreted and transmembrane
proteins
Initial step of neuronal polarization
and promotes the origin of
dendrites, controls dendrite
bifurcation and complexity of basal
dendrites
Neuropilin, Plexin, CRMP,
LKB1, GSK36, PI3 kinase,
mTor
Nakamura et al., 2009;
Tran et al., 2009;
Vodrazka et al., 2009;
Shelly et al., 2011
Notch Cell surface receptor Promotes dendritic complexity Delta, jagged, Nf-κB Breunig et al., 2007;
Bonini et al., 2011
Cadherin-catenin
cell
adhesion
complex
Cell adhesion complex,
participates in signaling and
regulation of actin cytoskeleton
N-cadherin, δ-catenin, p120ctn and
β-catenin promote dendritic
branching
Rac/Rho, erbin, Wnt,
αN-catenin, Arp3
Elia et al., 2006;
Arikkath et al., 2008;
Tan et al., 2010
SYNAPTIC SCAFFOLDING PROTEINS AND THEIR REGULATORS
Psd95 Postsynaptic density scaffolding
protein
Stop signal for proximal dendrite
branching
End-binding protein 3 (EB3) Charych et al., 2006
Cypin Protein that binds to the PDZ
domains of PSD-95 and
decreases localization of
PSD-95 at the postsynaptic
density
Promotes dendritic branching Tubulin, RhoA, BDNF, Snapin Firestein et al., 1999;
Akum et al., 2004;
Chen et al., 2005;
Chen and Firestein,
2007; Kwon et al.,
2011
LAP family of
proteins
Densin-180 and Erbin—
postsynaptic density proteins
Promotes dendritic branching Shank, δ-catenin Quitsch et al., 2005;
Arikkath et al., 2008
SIGNALING MOLECULES
Calmodulin
kinase 2b
Calcium/calmodulin—
dependent protein
kinases
Inhibitor of dendrite extension PCM1, cdc20 Puram et al., 2011
CRMP Collapsin response mediator
proteins
Suppression of inappropriate spatial
dendrite bifurcation during the
dendritic extension
Sema3A Niisato et al., 2012
CRP1 (Cysteine
rich protein 1)
Member of the cysteine-rich
protein (CRP) family which is a
subgroup of the LIM—domain
protein family
Dendritic growth Actin Ma et al., 2011
NDR (nuclear
Dbf2- related)
kinases
Subclass of the protein kinase
A/G/C family of kinases
Proximal dendrite growth and
branching
AP2 associated kinase Ultanir et al., 2012
(Continued)
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Arikkath Molecular mechanisms of dendrite morphogenesis
Table 1 | Continued
Factor/molecule Functional role Role in dendrite Components References
morphogenesis of pathway
Stk25
(Serine/Threonine
Kinase 25)
Kinase Length of apical and thickness of
basal dendrite
? Matsuki et al., 2010
CDK5 and related
proteins
Kinases Dendritic branching Variety of soluble factors,
cell surface receptors and
other signaling molecules,
including the Rho family of
GTPases
Cheung and Ip, 2007;
Cheung et al., 2007;
Zhang et al., 2010; Fu
et al., 2011; Su and
Tsai, 2011
REGULATORS OF THE CYTOSKELETON
Rac/Rho/Cdc42 Small GTP binding proteins Activation of Rac and Cdc42
promote the extension of neurites,
while activation of Rho mediates
the retraction of neurites
P120, cypin, Arf6 and other
signaling pathways
Hernandez-Deviez
et al., 2002; Luo,
2002; Leemhuis et al.,
2004; Elia et al., 2006;
Chen and Firestein,
2007
REGULATORS OF SECRETORY PATHWAY
Sar1 GTP binding protein that
functions in trafﬁcking from the
endoplasmic reticulum to the
golgi
Dendritic length ? Ye et al., 2007
CLIMP63 ER integral membrane protein Dendritic branching Phosphorylation dependent
microtubule association
Cui-Wang et al., 2012
Cul7Fbxw8 Cul7Fbxw8 forms an E3 ubiquitin
ligase
Dendritic arbor and length Grasp65, OBSL-1 Litterman et al., 2011
COMPONENTS OF CELL CYCLE MACHINERY
Origin recognition
complex
complex that allows for the
initiation of DNA duplication
during the cell cycle
Promotes dendritic growth and
branching
? Huang et al., 2005
Anaphase
promoting
complex (APC):
Ubiquitin ligase complex that
controls cell cycle transitions via
the coactivators Cdc20 and
Cdh1
Dendrite initiation and maintainance Cdc20, HDAC6, ld1 Kim et al., 2009
TRANSCRIPTIONAL MECHANISMS
Nf-κB Transcription factor Promotes dendrite length and
branching
Nerve growth factor, notch,
jagged
Gutierrez et al., 2005;
Bonini et al., 2011
CREB Transcription factor that
regulates gene expression
through binding cAMP response
elements
Promotes activity dependent
dendritic growth branching
CamKIV, CamKK, MAP
kinase pathway, Wnt2
Redmond et al., 2002;
Wayman et al., 2006
Cux1 Homeobox transcription factor Regulator of dendritic complexity p27Kip1 RhoA Li et al., 2010
Cux2 Homeobox transcription factor Regulator of dendritic complexity ? Cubelos et al., 2010
Neurogenin2 Basic-Helix-Loop-Helix (bHLH)
transcription factor
Regulation of dendritic polarity ? Hand et al., 2005
CREST (calcium-
responsive
transactivator)
Nuclear protein related to Syt. Promotes calcium dependent
dendritic growth
CBP (CREB binding protein),
nBAF chromatin remodeling
complexes
Aizawa et al., 2004;
Wu et al., 2007
Wnt FAMILY OF PROTEINS
The Wnt proteins are a family of secreted glycoproteins that bind
the frizzled receptor and result in the activation of the scaffolding
protein, Disheveled and subsequently the canonical or noncanonical
pathways. In the canonical pathway, this activation is
followed by activation of GSK3β, a serine-threonine kinase, which
in turn activates β-catenin mediated transcription. In the noncanonical
pathway, the Wnt proteins can directly activate the Rho
GTPases to modulate the actin cytoskeleton (Salinas and Zou,
2008). Wnt7b promotes dendritic complexity (Rosso et al., 2005)
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Arikkath Molecular mechanisms of dendrite morphogenesis
FIGURE 2 | Schematic of neuron showing various classes of molecules with some of the more recent examples that have been implicated in dendrite
arborization.
via the PDZ domain of Disheveled in association with Rac and
Jnk, but independent of the canonical signaling pathway and Rho.
In addition, Wnt-3a promotes the recruitment of Par1b/MARK2,
a polarity regulating kinase, to the membrane which then promotes
the phosphorylation of MAP2 which is selectively localized
to dendrites (Terabayashi et al., 2007). Interestingly, the expression
of another Wnt, Wnt2, that also promotes dendrite arborization
is regulated by synaptic activity (Wayman et al., 2006),
suggesting that Wnts may play key roles in the regulating dendrite
morphogeneis in an activity dependent manner.
EPHRINS AND Eph RECEPTORS
The Eph receptor tyrosine kinases and their ligands, the ephrins,
play critical roles in various aspects of axon and synapse development
and function. The Eph receptor tyrosine kinases are
subdivided into two major families, the EphA and EphB. The
ephrin ligands are anchored to the plasma membrane via
a GPI linked anchor (Ephrin-A) or transmembrane domain
(Ephrin-B). Interestingly, the Eph-Ephrin signaling is bidirectional
and both forward and reverse signaling mechanisms are
important in various aspects of CNS development and function
(Klein, 2009). Indeed, loss of EphB1, EphB2 and EphB3 in
a mouse model results in a reduction in dendritic arborization
(Hoogenraad et al., 2005) in mature neurons, suggesting that
Ephs play important roles in regulating dendrite arborization.
This can be partly attributed to the necessity of EphB to be trafﬁcked
to the surface membrane via a KIF5 (a microtubule motor
protein) and GRIP1 (glutamate receptor interacting protein 1)
dependent mechanism (Hoogenraad et al., 2005).
SEMAPHORINS
Semaphorins form a large family of a group of proteins that
include both secreted and transmembrane proteins. The major
receptors for Semaphorins are members of the Plexin family
of transmembrane proteins. The Neuropilins may also serve as
coreceptors for semaphorins. While several members of the family
play critical roles in axon guidance (Kolk et al., 2009) and
spine morphogenesis (Tran et al., 2009) and dendrite guidance,
it is now becoming clear that multiple semaphorins also regulate
dendrite outgrowth and architecture at different stages
during development. Recent studies indicate that Sema3A regulates
the initial step of neuronal polarization and promotes
the origin of dendrites (Shelly et al., 2011), while suppressing
axon formation, both in vivo and in vitro. Mechanistically,
Sema3A promotes the elevation of cGMP, but reduces the levels
of cAMP and activity of protein kinaseA. Interestingly,
loss of Sema3A increases the bifurcation of dendrites within
the stratum pyramidale (Nakamura et al., 2009). Sema3A also
promotes the complexity of basal dendritic arbors via neuropilin2
and PlexinA3 (Tran et al., 2009). Sema4D promotes
dendritic branching in hippocampal neurons via the PlexinB1
receptor, PI3 Kinase and mTor pathways (Vodrazka et al.,
2009).
NOTCH
Notch is a cell surface receptor that when cleaved releases an intracellular
fragment that translocates to the nucleus and regulates
gene expression. Two families of ligands, Delta and Jagged are
known to activate Notch. Signaling via the Notch receptor has
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Arikkath Molecular mechanisms of dendrite morphogenesis
FIGURE 3 | Four examples of molecules from different classes
that regulate dendritic branching. Knockdown of the postsynaptic
density proteins, Erbin (DIV 11–17) or regulator of postsynaptic
proteins, Cypin (DIV 5–10), or a component of the Cadherin-Catenin
cell adhesion complex, δ-catenin (DIV 11–17) result in a compromise
in dendritic branching. However, the addition of BDNF (25 ng/ml at
DIV 7–10) to hippocampal neurons increases neurite outgrowth and
branching.
an inhibitory effect on dendrite outgrowth. In cortical neurons,
overexpression of a dominant negative Notch or knockdown leads
to decreased dendritic branching (Breunig et al., 2007; Bonini
et al., 2011) Overexpression of Notch leads to decreased average
dendritic length, but increased complexity. Interestingly ablating
in vivo expression of Notch in glia using genetic techniques results
in a compromise in the dendritic complexity of newborn neurons
in maturing hippocampal neurons (Breunig et al., 2007) suggesting
that a complex role for Notch in regulating dendritic
branching in vivo.
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Arikkath Molecular mechanisms of dendrite morphogenesis
CADHERIN-CATENIN CELL ADHESION COMPLEX
The Cadherin-Catenin cell adhesion complex, comprising the
transmembrane domain containing protein Cadherin with its
associated cytosolic Catenins, mediates cell adhesion. It is now
clear Cadherins and Catenins play critical roles in regulating
the dendritic arbor. N-Cadherin is required for activity dependent
increase in dendrite arborization, a functional role that
requires it to regulate the actin cytoskeleton via the cytosolic αN
catenin and Arp3 (Tan et al., 2010). δ-catenin, and P120ctn, both
cytosolic catenins that bind to the juxtamembrane domain of cadherin,
also play critical roles in regulating dendrite arborization
although through different regulatory pathways. Loss or knockdown
of P120ctn leads to a decrease in dendritic branching. This
is accompanied by an increase in active RhoA and decrease in
active Rac suggesting that these small G proteins play critical roles
in the ability of p120ctn to regulate dendrite branching (Elia et al.,
2006). However, loss of δ-catenin reduces dendrite branching
with no effects on the levels of active Rac and RhoA, suggesting
that p120ctn and δ-catenin utlize different mechanisms to regulate
dendrite branching. Consistently, Erbin, a LAP family protein
is known to be an upstream regulator of δ-catenin in regulating
dendrite branching and functions by promoting proper localization
of δ-catenin (Arikkath et al., 2008). Additionally, β-catenin
overexpression promotes activity dependent dendrite branching
through a Wnt dependent pathway.
SYNAPTIC SCAFFOLDING PROTEINS AND THEIR
REGULATORS
A number of synaptic scaffolding molecules, predominantly
localized to postsynaptic densities, have been identiﬁed to be critical
regulators of dendritic morphogenesis. A number of these
appear to inﬂuence dendritic arborization by directly regulating
the actin and microtubule cytoskeleton.
PSD-95 (POSTSYNAPTIC DENSITY PROTEIN-95)
PSD-95 is a crucial scaffolding protein, which assembles signaling
complexes at excitatory synapses. Its protein-protein interaction
motifs, called PDZ domains (Kim and Sheng, 2004), bind to other
PDZ domains and to various receptors and ion channels that contain
the C-terminal PDZ binding consensus sequence T/S-X-V/I.
The regulation of PSD-95 expression/degradation, clustering, and
localization is important for neurons establishing and maintaining
proper synaptic connections (Matus, 2000). In addition to its
synaptic function, PSD-95 also exhibits a nonsynaptic function
during hippocampal neuron dendritic development (Charych
et al., 2006). PSD-95 acts as a stop signal for proximal dendrite
branching by disrupting microtubule organization (Charych
et al., 2006; Sweet et al., 2011). PSD-95 directly interacts with
a proline-rich region of end-binding protein 3 (EB3) by its src
homology 3 (SH3) domain, and alters microtubule structure
(Sweet et al., 2011). Taken together, PSD-95 regulates dendritic
morphology in young neurons.
CYPIN (CYTOSOLIC PSD-95 INTERACTOR)
Cypin was originally identiﬁed as a protein that binds to the
PDZ domains of PSD-95 and decreases localization of PSD-95
at the postsynaptic density (Firestein et al., 1999). It localizes
to spine necks and dendrites. Cypin increases dendrite branching
when overexpressed in hippocampal neurons. Cypin directly
binds to tubulin heterodimers and promotes microtubule assembly
(Akum et al., 2004), and thus regulates dendrite branching
via cytoskeletal rearrangement. In addition, Snapin antagonizes
tubulin binding to cypin, thus changing dendrite branching
patterns (Chen et al., 2005). RhoA controls dendrite branching
by regulating cypin protein levels (Chen and Firestein,
2007). Moreover, BDNF increases proximal dendrites by CREBdependent
transcriptional activation of cypin (Kwon et al., 2011).
MEMBERS OF THE LAP FAMILY OF PROTEINS
Two members of the LAP (leucine rich and PDZ domain containing)
family of proteins, namely erbin and densin-180 that
localize to synapses have been implicated in dendritic branching.
Knockdown of erbin reduces total dendritic length, while
overexpression of densin-180 promotes dendritic branching and
complexity (Arikkath et al., 2008). While erbin regulates dendritic
branching through δ-catenin, a component of the cadherincatenin
cell adhesion complex, the effects of densin-180 are
mediated by shank and possibly δ-catenin (Quitsch et al., 2005).
SIGNALING MOLECULES
Signaling molecules participate in dendritic branching, at least
in part by regulating the cytoskeleton. They may also function
as transducers of information from cell surface receptors to control
dendrite arborization. While examples of individual signaling
molecules that control dendrite arborization are known, it is
not always clear what the regulators that control these signaling
pathways are.
CALMODULIN KINASE IIB
The calcium/calmodulin-dependent protein kinases (CaMKs)
in the brain are predominantly composed of the α and β
isoforms which function by forming homo or heterodimers.
Knockdown of CamkIIβ leads to an increase in dendrite extension
throughout development. This functional role is independent of
CamKIIα and CamkIIβ controls dendritic branching by localizing
at the centrosome via its association with PCM1, a centrosomal
targeting protein. At the centrosome, CamkIIβ phosphorylates
cdc20 (coactivator of APC), thus inhibiting its activity and leading
to dendrite retraction (Puram et al., 2011).
CRMP (COLLAPSIN RESPONSE MEDIATOR PROTEINS)
The CRMPs are a family of cytosolic phosphoproteins. The family
consists of ﬁve known members namely CRMP 1–5. Some
of these members have been implicated in the signaling mechanisms
underlying Sema3 mediated axon guidance. Recent studies
however suggest that their functional roles extend to the control
of speciﬁc aspects of dendrite arborization. In mice that
are genetically null for CRMP4, hippocampal pyramidal CA1
neurons have increased bifurcation in the stratum pyramidale
layer, suggesting a critical role for CRMP4 in suppression of
inappropriate spatial dendrite bifurcation during the dendritic
extension (Niisato et al., 2012). In addition, loss of CRMP4 leads
to an increase in dendritic branch points. These effects are mediated,
at least in part, by Sema3A since loss of CRMP4 leads to
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Arikkath Molecular mechanisms of dendrite morphogenesis
a compromise in the ability of Sema3A to promote dendritic
branching.
CYSTEINE-RICH PROTEIN1
CRP1 is a member of the cysteine-rich protein (CRP) family
which is a subgroup of the LIM-domain protein family.
Knockdown of CRP1 leads to a decrease in dendritic growth during
development, while overexpression does not alter the total
neurite length. This functional ability is mediated in part by its
actin bundling activity (Ma et al., 2011).
NDR (NUCLEAR DBF2-RELATED) KINASES
The NDR kinases are a subclass of the protein kinase A/G/C
family of kinases. The NDR family of proteins control cellular
morphognesis in various cell types, however recent evidence indicates
that NDR1 and 2 contribute to dendrite morphogenesis. The
activity of both NDR1 and 2 inhibits proximal dendrite growth
and branching. These effects are mediated by the AP2 associated
kinase, which functions downstream of NRD1/2 in regulating
dendritic branching (Ultanir et al., 2012).
Stk25 (SERINE/THREONINE KINASE 25)
Knockdown of stk25 promotes an increase in the length of the
apical dendrite coupled with increased thickness of the basal
dendrite (Matsuki et al., 2010).
Cdk5 AND RELATED PROTEINS
Cdk5 is a serine/threonine kinase that functions in multiple
aspects of neuronal development. The activation of cdk5 is dependent
on two activators, p35, and p39, which are predominantly
expressed in neurons (Cheung and Ip, 2007). Cdk5 regulates neurite
outgrowth by cooperating with a variety of soluble factors
(Cheung et al., 2007), cell surface receptors and other signaling
molecules, including the Rho family of GTPases (Su and
Tsai, 2011). Knockdown or inhibition of the kinase activity of
cdk5 inhibits dendrite growth and branching while inhibition
of its ability to be S-nitrosylated increases dendritic branching
(Zhang et al., 2010). Pctaire1, a cyclin-dependent kinase
(Cdk)-related protein, also plays a key role in regulating dendrite
arborization, both during development and at later stages.
This functional role is mediated by its ability to be phosphorylated
by cdk5 and its ability to function as a kinase (Fu et al.,
2011).
REGULATORS OF THE CYTOSKELETON
Modulation of the cytoskeleton is key in eliciting structural
changes in dendrites. Consequently, regulators of the cytoskeleton
play a key role in dendrite arborization.
Rac/Rho/Cdc42
Rac, Rho, and Cdc42 are included in a family of small GTPases.
Signaling by one or more of these small GTPases appears to
play a role in dendrite initiation, growth and dendrite branching
(Luo, 2002; Leemhuis et al., 2004). Activation of Rac and
Cdc42 promote the extension of neurites, while activation of
Rho mediates the retraction of neurites. These small GTPases
also cooperate with other signaling pathways to regulate dendrite
arborization, including a component of the cadherin-catenin cell
adhesion complex (Elia et al., 2006), a postsynaptic density component,
cypin (Chen and Firestein, 2007) and a member of the
ADP-ribosylation factor (ARF) family of small GTPases, Arf6
(Hernandez-Deviez et al., 2002). These small GTPases function
through a variety of complex molecular pathways (de Curtis,
2008; Chen et al., 2012) to control dendrites and other aspects
of neuronal morphology and function and have been implicated
in neurological disorders (Nadif Kasri and Van Aelst, 2008).
REGULATORS OF SECRETORY PATHWAY
In neurons, the secretory pathway that comprises the endoplasmic
reticulum Golgi and post Golgi intermediates and ER and
Golgi outposts contribute to the dendritic plasma membrane.
Consequently proteins that control various aspects of secretory
trafﬁcking have been implicated in dendritic arborization
(Ye et al., 2007).
Sar1
Sar1 is a GTP binding protein that functions in trafﬁcking from
the endoplasmic reticulum to the Golgi. Knockdown of Sar1
during dendritic development (Ye et al., 2007) reduces the total
dendritic, but not axon length, indicating that the secretory
trafﬁcking from the Golgi is an important contributor to the
dendritic membrane.
CLIMP63
CLIMP63 is an ER integral membrane protein. Its binding to
microtubules is regulated by PKC-dependent phosphorylation.
Phosphorylation of CLIMP63 prevents association with microtubules.
In neurons, expression of phosphorylation deﬁcient form
of CLIMP63 results in fewer proximal dendritic branches, while
expression of phosphomimetic form or RNAi mediated knockdown
promotes dendritic branching (Cui-Wang et al., 2012).
These effects are directly related to the ability of CLIMP3 to
regulate the complexity of the ER.
Cul7Fbxw8 UBIQUITIN LIGASE
Fbxw8 is an F-box protein that assembles with the scaffold protein,
Cul7. The Cul7Fbxw8 forms an E3 ubiquitin ligase that
localizes to the Golgi apparatus in neurons. Recent studies indicate
that it is required for growth and elaboration of dendrites
in hippocampal neurons. Knockdown of Fbxw8 or Cul7 leads to
a simpliﬁcation of the dendritic arbor accompanied by a reduction
in the total dendritic length and increased dispersion of the
Golgi apparatus. The Obscurin-like 1, OBSL1, protein controls
the localization of Cul7 to the Golgi apparatus. Further, Grasp65,
a Golgi protein that regulates secretory trafﬁcking, is a substrate
for Cul7Fbxw8 in organizing the Golgi structure and dendrite
elaboration (Litterman et al., 2011).
COMPONENTS OF THE CELL CYCLE MACHINERY
Hippocampal and cortical neurons are postmitotic, but surprisingly
proteins that control various aspects of the cell cycle
machinery have been detected in these neurons. Some of these
have been implicated in dendritic branching, suggesting that evolutionary
adaptations might promote the use of the same protein
in different cellular contexts thus promoting optimal utilization
of existing resources.
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Arikkath Molecular mechanisms of dendrite morphogenesis
ORIGIN RECOGNITION COMPLEX
The origin recognition complex is composed of a hexameric protein
complex that allows for the initiation of DNA duplication
during the cell cycle. However, it has recently become evident
that components this complex are expressed in postmitotic adult
hippocampal and cortical neurons. Knockdown of the Orc3 in
hippocampal neurons leads to a severe reduction in dendritic
growth and branching, a functional role that is mediated by its
Walker ATPase motif (Huang et al., 2005).
ANAPHASE PROMOTING COMPLEX (APC)
The APC is an ubiquitin ligase complex that controls cell cycle
transitions via the coactivators Cdc20 and Cdh1. It is now evident
that the complex controls dendrite arborization in developing
and mature neurons. Knockdown of cdc20 at early or late stages
of development leads to a simpliﬁcation of the dendritic arbor
accompanied by a decrease in total dendritic length, suggesting
that cdc20 controls both dendrite initiation and maintenance.
Interestingly, the localization of cdc20 at the centrosome is critical
for its ability to regulate dendrite development. Its functional role
is promoted by an interaction with HDAC6, a class IIb histone
deacetylase, while the helix-loop-helix protein Id1 is a substrate
for the complex (Kim et al., 2009). The APC/cdc20/HDAC6/Id1
is one of the few known pathways that operate at the centrosome
to control dendrite extension.
TRANSCRIPTIONAL MECHANISMS
Transcriptional mechanisms are key in regulating dendritic outgrowth,
since such mechanisms can promote long-term changes
by controlling gene expression programs comprising of several
genes. While several transcription factors that regulate dendrite
arborization have been identiﬁed, the challenge has been to identify
the cues that activate these factors and delineate the gene
expression programs that they coordinate.
NF-κB
Nuclear factor kB (NF-κB) is a ubiquitously expressed transcription
factor, whose functional roles vary with cell context and
dimerization (Gutierrez and Davies, 2011). The family consists
of ﬁve related proteins, c-Rel, RelB, p65, p50, and p52 that function
by hetero or homo dimerization and regulate gene expression
positively or negatively by binding to elements in the promoter
or enhancer regions of target genes. The iκB family of proteins
functions to bind the NF-κb and hold them in an inactive cytosolic
location. Activation of NF-κB is achieved by the removal of
the bound iκB and subsequent translocation of the activated
NF-κb to the nucleus. In neurons, the most common form of
NF-κb is the p65/p50 heterodimer. Inhibition of NF-κB signaling
or transcriptional activation reduces dendrite length in cortical
pyramidal layer2/3 neurons (Gutierrez et al., 2005). Similarly,
dendrite branching is compromised in cortical neurons from P50
null mice (Bonini et al., 2011). There appear to be at least two
signals that use NF-κB as a mediator to regulate dendritic arbors.
Addition of NGF to hippocampal neurons in culture reduces the
number of primary dendrites and promotes the elongation of
dendrites. Inhibition of NF-κB signaling perturbs these effects of
NGF, suggesting that NF-κB is a downstream regulator of NGF
induced dendrite arborization. In addition, Nf-κB also functions
in the Notch signaling pathway to regulate dendrite arborization.
Loss of the p50 subunit of NF-κB is accompanied by an increase in
the expression of Notch and Jagged1. Inhibition of Notch restores
the dendritic arborization deﬁcits in the P50 null neurons, suggesting
that Notch/Jagged1 function through NF-κB to regulate
dendrite branching (Bonini et al., 2011). However, the transcriptional
targets of NF-κB that control dendrite arborization are not
well deﬁned.
CREB (CYCLIC AMP RESPONSE ELEMENT-BINDING)
CREB is a transcription factor that controls gene expression via
binding to cAMP response elements (CRE). CREB is critical for
activity induced dendritic growth and branching. This functional
role is mediated in part by the ability of CREB to serve
as a downstream effector of CamKIV (Redmond et al., 2002)
and CaM-dependent protein kinase kinase via components of
the MAP kinase pathway and regulate the expression of Wnt2
(Wayman et al., 2006).
Cux1
The Cux proteins are a family of homeobox transcription factors
that control cell proliferation and differentiation. Of these,
Cux1 and Cux2 are expressed in central neurons. Overexpression
of Cux1, but not Cux2, simpliﬁes the dendritic morphology while
knockdown enhances dendritic complexity in cultured cortical
neurons. In this cell culture model, Cux1 functions as a transcriptional
repressor of p27Kip1, thus knockdown of Cux1 leads
to increased levels of p27Kip1 which in turn regulates the small
GTP binding protein, RhoA (Li et al., 2010). Interestingly, however,
murine models lacking either Cux1 or Cux2 layers 2–3
cortical neurons have simpliﬁed dendritic morphology at P60
(Cubelos et al., 2010). In utero introduction of shRNAs to Cux1
and Cux2 also results in a decrease in dendritic complexity. It
is unclear how these differences in results can be reconciled and
may perhaps reﬂect the inﬂuence of other unknown factors that
contribute to the functional roles of Cux1 and Cux2 in dendrite
morphogenesis.
NEUROGENIN 2
Neurogenenin 2 is a member of the basic-Helix-Loop-Helix
(bHLH) transcription factors. The expression of mutant forms of
neurogenin2 that either cannot be phosphorylated or cannot bind
DNA in early migrating neurons results in a multipolar dendritic
morphology, with no distinct apical dendrite (Hand et al., 2005).
CREST (CALCIUM-RESPONSIVE TRANSACTIVATOR)
CREST is a nuclear protein related to Syt. Loss of CREST in a
murine model results in a severe compromise in calcium dependent
dendritic growth (Aizawa et al., 2004). These effects are
mediated by its ability to bind CBP (CREB binding protein)
and the nBAF neuron-speciﬁc chromatin remodeling complexes
(Wu et al., 2007).
DENDRITIC ARCHITECTURE AND NEUROLOGICAL
DISORDERS
Consistent with the necessity of appropriate dendritic architecture
for higher order brain functions, including learning and
memory, deﬁciencies in the architecture of dendrites have been
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Arikkath Molecular mechanisms of dendrite morphogenesis
observed in a variety of neurodevelopmental, neurodegenerative
and neuropsychiatric disorders (Kulkarni and Firestein, 2012).
For example, decreased dendritic branching in CA1 and CA4 hippocampal
neurons occurs in patients with autism and neurons
from patients with Rett syndrome. Similarly, altered dendritic
arborization and decreased expression of glutamate receptors
have been observed in CA3 hippocampal neurons of patients
with schizophrenia (Kolomeets et al., 2007). Speciﬁc dendritic
alterations are seen in cortical neurons in those with Rett syndrome.
Decreased dendrite number have also been observed in
patients with Alzheimer’s Disease (Couch et al., 2010), and Down
Syndrome (Elston, 2003).
In addition to the neurodevelopmental and neurodegenerative
disorders, other neurological disorders may be associated with
alterations in the dendritic arbor that compromise higher order
functions, including cognition. For example, recurrent seizures
during development in mice lead to a suppression of the growth
of dendrites in the CA1 region (Casanova et al., 2012) and may
thus contribute to the cognitive deﬁcits observed in childhood
epilepsy. Pathological conditions associated with other conditions
that lead to alterations in higher order brain functions, also
cause alterations in dendritic architecture (Liston et al., 2006).
For example, stress paradigms in rats results in the retraction
of the apical dendrite and branch number (Radley et al., 2005).
Administration of nicotine results in an increased dendritic complexity
in the insular cortex, associated with enhanced dendritic
length and addition of new dendritic branches (Ehlinger et al.,
2012). Prenatal exposure to cocaine or heroin in mice results in
an increase or decrease respectively in dendritic arbors in the
somatosensory cortex and cause impairments in short-term spatial
memory (Lu et al., 2012). Neuropathic pain, associated with
depression and cognitive decline, in a rat model is associated with
an increase in the length and number of branches of basal dendrites
(Metz et al., 2009). Thus, an abnormality in the dendritic
arbor is a common theme seen in disorders of the central nervous
system and these aberrations may be directly linked to deﬁciencies
in higher order brain functions.
SUMMARY, OUTSTANDING QUESTIONS, AND CHALLENGES
A variety of different factors contribute to create and maintain the
complex dendritic architecture that is key to higher order brain
functions, including learning and memory. Each of these factors
do not function in isolation, but cooperate with one or more of
the other known or unknown molecules in a complex manner to
control the formation and maintenance of dendritic architecture.
For example, δ-catenin, a component of the cadherin-catenin cell
adhesion complex regulates dendritic architecture during development
via its functional interaction with an upstream activator,
erbin (Arikkath et al., 2008). It is highly unlikely that erbin is
its only upstream activator. In addition, it likely interacts with
a variety of other unknown cellular factors to control the actin
cytoskeleton to ultimately affect dendritic arbors. These factors
remain unknown. It is also likely that various classes of these
proteins interact with each other dynamically, so that their interactions
and functional roles are aligned with the developmental
requirements for sculpting or adult requirements for maintaining
the dendritic arbor. In addition, these interactions and functional
roles are likely regulated in an activity dependent manner to allow
for dynamic control of dendritic architecture aligned with neuronal
activity. Localized interactions of some of these classes of
proteins may also inﬂuence speciﬁc architectural alterations, for
example the generation and maintenance of secondary dendrites.
Thus the generation, sculpting and maintenance of the dendritic
arbor is a complex process that requires coordination and
cooperation of various classes of proteins. Many of these proteins
and their mechanisms of action and their complex interactions
with other known and unknown factors probably remain undeﬁned.
Future efforts would likely be directed at examining and
deﬁning these complex interactions and their roles in detecting
and transducing information to the cytoskeleton to contribute to
the generation and maintenance of the dendritic arbor.
It is now clear that the structure of the dendritic arbor is critical
for signal integration, appropriate synapse formation and neural
circuit function. It is also clear that several different classes
of proteins play critical roles in determining the initiation and
maintenance of the dendritic arbor. Many more probably remain
to be identiﬁed. Moreover, dendritic arbors are not homogeneous
structurally and functionally and it is evident that several
mechanisms operate to control various aspects of branching. For
example, molecular effectors that regulate either more proximal
or more distal branching are known. Mechanisms that control the
specialization of the apical vs. basolateral dendrites exist. Many
challenges, however, remain in our understanding of the molecular
control of dendritic arborization. What are the signals that
allow initiation of dendrite formation? How are these integrated
with neuronal migration? What are the key signals that coordinate
the formation of the apical vs. basal dendrite? How are these
dendritic polarities maintained through the lifetime of the animal?
What are the factors that control layer speciﬁc branching of
the dendritic arbor and prevent inappropriate branching? How
do the different molecular pathways cross-talk to ensure the generation
and maintenance of appropriate arborization? How are all
these events coordinated with neuronal activity and neural development?
Can manipulation of these pathways provide therapeutic
avenues for neurodevelopmental disorders and acute neurological
disorders that result in neuronal loss or compromise in neuronal
architecture and function?
We are now in an exciting technological age where powerful
tools are becoming increasingly available to address fundamental
problems in neurobiology. These include tools that allow
for genetic manipulation of murine models, control of neuron
speciﬁc activation or inhibition in vivo, for example using
optogenetic tools (Tye and Deisseroth, 2012), advanced imaging
molecules (Weimer et al., 2012) and techniques and high efﬁciency
gene sequencing techniques. These tools should allow us
to develop new and critical insights into how the dendritic arbor
develops and is maintained through life, how dendritic arborization
contributes to neural circuit formation and function and
how aberrations in dendritic arbors contribute to the pathology
of various neurological disorders.
ACKNOWLEDGMENTS
We thank Li Yuan for assistance with ﬁgures and Dr. Munjin Kwon
for some of the images in Figure 3.
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Arikkath Molecular mechanisms of dendrite morphogenesis
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Conﬂict of Interest Statement: The
author declares that the research
was conducted in the absence of any
commercial or ﬁnancial relationships
that could be construed as a potential
conﬂict of interest.
Received: 03 October 2012; accepted: 08
December 2012; published online: 28
December 2012.
Citation: Arikkath J (2012) Molecular
mechanisms of dendrite morphogenesis.
Front. Cell. Neurosci. 6:61. doi: 10.3389/
fncel.2012.00061
Copyright © 2012 Arikkath. This is
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