Molecular basis of dendritic arborization

Abstract

The pattern of dendritic branching along with the receptor and channel composition and density of synapses regulate the electrical properties of neurons. Abnormalities in dendritic tree development lead to serious dysfunction of neuronal circuits and, consequently, the whole nervous system. Not surprisingly, the complicated and multi-step process of dendritic arbor development is highly regulated and controlled at every stage by both extrinsic signals and intrinsic molecular mechanisms. In this review, we analyze the molecular mechanisms that contribute to cellular processes that are crucial for the proper formation and stability of dendritic arbors, in such distant organisms as insects (e.g. Drosophila melanogaster) amphibians (Xenopus laevis) and mammals.

Full text

Review Acta Neurobiol Exp 2008, 68: 264–288
© 2008 by Polish Neuroscience Society - PTBUN, Nencki Institute of Experimental Biology
INTRODUCTION
Dendrites are the main site of information input
into neurons, and different type of neurons have dis-
tinctive and characteristic dendrite branching pat-
terns. Advances in electrophysiology and computa-
tional modeling have clearly shown that dendritic
arbor shape is one of the crucial factors determining
how signals coming from individual synapses are
integrated (Segev and London 2000, Gulledge et al.
2005). Several neuropathologic conditions are charac-
terized by abnormalities in dendritic tree structure,
including a number of mental retardation syndromes
(such as Down’s, Rett’s as well as Fragile X syn-
drome; for review see: Kaufmann and Moser 2000),
schizophrenia (Harrison 1999), and neurodegenera-
tive diseases (for review see Anderton et al. 1998). In
addition, animal studies reveal that even mild, pro-
longed stress can induce the shrinkage of hippocam-
pal dendritic fields, dendritic regression and loss of
dendritic
spines (Wood et al. 2004, Chen et al. 2008).
Dendritic arbor development is a complex, multi-
step process (Fig. 1), which generally can be divided,
into several different, although partially overlap-
ping, stages: (i) neurite initiation, outgrowth and
guidance; (ii) branching and synapse formation, and
(iii) stabilization (Kossel et al. 1997, Wu et al. 1999,
Portera-Cailliau et al. 2003, Williams and Truman
2004; for review see: Scott and Luo 2001). Although
the time scale of these steps differs between species,
the sequence of events seems to be very similar.
Initial dendrite growth is relatively slow, and a very
fast period of dendritic extension follows. For exam-
ple, total dendritic length increased from ~50 to 100
µm during first 24 h of X. laevis tectal neurons den-
dritic arbor development but almost 4-fold increase
was observed during the next 48 hours (Wu et al.
1999). Subsequently, dynamic dendritic branching
occurs, which combined with neuronal activity and
synapse formation, leads to the establishment of a
well-developed dendritic arbor. Stabilization of the
dendritic arbor occurs over a long period of time
(Wu et al. 1999, Williams and Truman 2004). While
the development of dendritic tree associates with
high rates of branch additions and retractions, the
mature dendritic arbor is less plastic with a very low
branch turnover under basal conditions (Wu et al.
1999). Nevertheless, dendritic arbors in the mature
nervous system preserve some degree of plasticity.
Increased branching was observed in the nucleus
Molecular basis of dendritic arborization
Malgorzata Urbanska
1,2
, Magdalena Blazejczyk
1,3
, and Jacek Jaworski
1
*
1
International Institute of Molecular and Cell Biology, Warsaw, Poland, *Email: jaworski@iimcb.gov.pl;
2
Warsaw
University of Life Sciences, Warsaw, Poland;
3
Laboratory of Molecular Neurobiology, Nencki Institute, Warsaw, Poland
The pattern of dendritic branching along with the receptor and channel composition and density of synapses regulate the
electrical properties of neurons. Abnormalities in dendritic tree development lead to serious dysfunction of neuronal
circuits and, consequently, the whole nervous system. Not surprisingly, the complicated and multi-step process of dendritic
arbor development is highly regulated and controlled at every stage by both extrinsic signals and intrinsic molecular
mechanisms. In this review, we analyze the molecular mechanisms that contribute to cellular processes that are crucial for
the proper formation and stability of dendritic arbors, in such distant organisms as insects (e.g. Drosophila melanogaster),
amphibians (Xenopus laevis), and mammals.
Key words: dendritic arbor, signal transduction, cytoskeleton dynamics, protein synthesis, membrane trafficking
Correspondence should be addressed to J. Jaworski,
Email: jaworski@iimcb.gov.pl
Received 9 April 2008, accepted 12 May 2008

Molecular basis of dendritic arborization 265
Fig. 1. Development of dendritic arbor consists of several overlapping stages
Fig. 2. Dendritogenesis is a process strictly controlled by the combination of an intrinsic genetic program and extracellular
signals causing changes in the cytoskeleton, macromolecule synthesis and membrane turnover. Several changes occur
either globally or only locally in dendrites.

266 M. Urbanska et al.
accumbens and the caudate-putamen upon repeated
cocaine administration (Zhang et al. 2006), and in
the spinal cord in response to a long-term locomotor
training accompanying recovery after spinal cord
injury (Gazula et al. 2004).
The complex processes of dendritic arbor devel-
opment and stabilization must be highly orchestrated
at the molecular level. Recent advances in genetic
manipulations of neuronal cells helped to reveal a
complicated interacting network of dozens, if not
hundreds, of proteins involved in signal transduc-
tion, macromolecule synthesis, cytoskeleton rear-
rangements and intracellular trafficking of proteins
and membranes (Fig. 2). These processes are regu-
lated by both an intrinsic genetic program and a
wide variety of extracellular signals, either globally
at the whole-cell level or locally in dendrites.
The aim of this review is to present readers, espe-
cially those not familiar with topics of neuronal
development and morphology, selected aspects of
the molecular biology underlying the complex pro-
cess of dendritic arbor formation. First, we discuss
the impact of a genetic program and signals from the
extracellular environment on a dendritic arboriza-
tion. Second, we describe a role for intracellular
events such as signal transduction, cytoskeleton
dynamics, transcription, translation, and cellular
membrane turnover in translating genetic and envi-
ronmental instructions to the final shape of a den-
dritic arbor.
GENETIC PROGRAM AND EXTRINSIC
CUES IN DENDRITIC ARBOR
DEVELOPMENT
Genetic program – role of transcription
factors in dendritogenesis
The genetic program is executed by transcription
factors (TFs), several of which determine dendritic
patterning independently from extracellular cues.
The best examples come from developmental stud-
ies of the Drosophila melanogaster neurons. Hamlet
is a TF expressed during development in the exter-
nal sensory neurons (es) of the Drosophila periph-
eral nervous system (Moore et al. 2002). Neurons
belonging to this particular class develop only a
single dendrite and Hamlet expression prevents the
es neurons from acquiring a morphology character-
istic of multiple dendrite (md) neurons. Knockdown
of hamlet in precursors of the es neurons results in
transformation of these cells to the md neurons with
complex dendritic trees. Conversely, overexpres-
sion of Hamlet in the md neurons causes growth of
only a single dendrite. Hamlet can act alone, but the
complex pattern of the dendritic arborization (da)
subclass of the md Drosophila neurons requires the
concerted action of several TFs. Combinatorial
expression of Cut, Abrupt, and Spineless define
dendritic arbor complexity in the da neuron sub-
classes. Class I neurons, with relatively simple den-
dritic arbors, express high levels of Abrupt and
Spineless but no Cut. Highly-branched Class IV
neurons express intermediate levels of Cut, high
levels of Spineless, and lack expression of Abrupt
(Parrish et al. 2007). Recent work by Parish and
coauthors (2006) identified dozens of TFs that are
critical for proper dendritic arborization of the
Class I da neurons; however, it is difficult to distin-
guish which of them act autonomously, executing
the intrinsic genetic program independently from
extracellular cues, and which respond to extracel-
lular instructions. For example, BAP55, Brm,
BAP60 and Snr1, proteins identified during this
screen are elements of Brg/Brm associated factor
complex that regulates transcription and dendritic
branching in an activity-dependent manner (Wu et
al. 2007).
Despite examples of autonomously acting TFs in
Drosophila during specification of dendritic arbor
morphology, less is known about similar proteins in
the mammalian nervous system. One example is
Neurogenin 2 (Ngn2), a basic helix-loop-helix factor
that defines a specific pattern of dendritic arboriza-
tion in pyramidal neurons in cerebral cortex (Hand
et al. 2005). Cobos et al. (2005, 2007) showed that
Dlx homeobox transcription factors regulate, cell
autonomously, dendritic arborization of cortical
interneurons. Interneuron precursors, derived from
the Dlx1 knockout mice, grafted to the brains of
wild-type mice, developed about 40% less dendritic
branches, which suggests that even in a normal envi-
ronment the Dlx1 -/- interneurons do not develop
properly (Cobos et al. 2005). In double Dlx1/2
mutants, long and poorly branched dendrites and
axons develop prematurely, disturbing migration and
proper positioning of the interneurons (Cobos et al.
2007).

Molecular basis of dendritic arborization 267
Table I
Extracellular signals controlling shape of dendritic arbor
Protein/Protein
complex
Effect on dendrites Nervous
system
structure
/Species
Reference
Neuronal activity related
AMPAR DN-Ox – decreased TDL, TDBTN and dendritic
arbor (ShA) simplification
Inh - decreased branch addition after light exposure
optic tectum
/X. laevis
Haas et al. 2006
Sin et al. 2002
NMDAR Inh - decreased branch addition after light
exposure
optic tectum
/X. laevis
Sin et al. 2002
VGCC KCl application – increased TDL, TDBTN,
complexity
hippocampus,
cortex,
cerebellum/rat,
mouse
Redmond et al. 2002, Yu
and Malenka 2003,
Gaudilliere et al. 2004,
Chen et al. 2005, Wayman
et al. 2006, Wu et al. 2007
GABAR GABA application – increased TDL and number
of primary dendrites
Inh – decreased TDL and number of primary
dendrites
cortical
subventricular
zone-derived,
olfactory bulb
/rat
Gascon et al. 2006
CaSR DN-Ox – decreased TDL, dendritic arbor
simplification (ShA)
hippocampus
/mouse
Vizard et al. 2008
Diffusable cues
agrin Agrin application – increased TDL and number
of 2
nd
order dendrites
hippocampus
/rat
Mantych and Ferreira
2001
BDNF BDNF application – increased TDL
WT-Ox – increased dendritic arbor complexity
(ShA)
hippocampus,
cortex/rat
Wirth et al. 2003, Dijkhuizen
and Ghosh 2005, Jaworski et
al. 2005, Takemoto-Kimura
et al. 2007
BMP BMP7 application – increased TDL, number of
dendrites, TDBTN
SCG,
hippocampus
/rat
Withers et al. 2000, Guo et
al. 2001, Lein et al. 2007
cpg15 WT-Ox – increased TDL, complexity (ShA),
growth rate
optic tectum
/X. laevis
Nedivi et al. 1998
Semaphorin3a Sema3A application – increased DBPN cortex/mouse Morita et al. 2006

268 M. Urbanska et al.
Role of extracellular signals in the control of
dendritic arborization
Evidence for the importance of extracellular guid-
ance for dendritic arborization is overwhelming.
Depending on the developmental stage, combinations
of (i) diffusible cues, (ii) cell contacts, and (iii) neu-
ronal activity were shown to control dendritic arboriza-
tion, plasticity and stability (for review see: McAllister
2000, Wong and Ghosh 2002, Jan and Jan 2003,
Parrish et al. 2006) (Table I).
Diffusible cues are numerous and a few examples are
agrin (Mantych and Ferreira 2001), brain-derived neu-
rotrophic factor (BDNF) (McAllister et al. 1995, Horch
and Katz 2002, Tolwani et al. 2002, Wirth et al. 2003,
Jaworski et al. 2005), bone morphogenetic protein fam-
ily members (Withers et al. 2000, Beck et al. 2001, Guo
et al. 2001, Lein et al. 2007), cpg15 (Nedivi et al. 1998),
reelin (Jossin and Goffinet 2007), semaphorins (Polleux
et al. 2000) and Slits (Whitford et al. 2002) (Table I).
Interactions of cell surface proteins like contactin
(Berglund et al. 1999), Delta and Notch (Sestan et al.
Slit Slit1 application – increased TDL, number of
dendrites, DBPN
cortex
/rat, mouse
Whitford et al. 2002
Reelin Reelin application – increased TDL and number
of branches
hippocampus
/mouse
Jossin and Goffinet 2007
Cell contacts
Celsr-2 KnD - dendritic arbor simplification (ShA) cortex,
hippocampus
/rat
Shima 2007
Celsr-3 KnD – increased dendritic arbor complexity
(ShA)
cortex,
hippocampus
/rat
Shima et al. 2007
Delta-Notch DN-Ox - decreased DBPN, increased average
dendrite length
CA-Ox - decreased average dendrite length
KnD – decreased DBPN, increased average
dendrite length
cortex/rat Redmond et al. 2000
Dscam KO – lost self-avoidance da
/D. melanogaster
Hughes et al. 2007,
Matthews et al. 2007, Soba
et al. 2007
EphrinB-EphB KO – decreased TDL, number of primary
dendrites and complexity
Inh – reduced number of primary dendrites
hippocampus
/rat, mouse
Hoogenraad et al. 2005
N-cadherin WT-Ox - increased TDBTN
DN-Ox – decreased TDBTN
hippocampus
/rat
Yu and Malenka 2003
(ADL) average dendrite length; (CA-Ox) overexpression of constitutively active mutant; (DBPN) dendritic branching
points number; (DN-Ox) overexpression of dominant negative mutant; (Inh) non genetic inhibition; (KO) knockout; (Knd)
knockdown; (SCG) superior cervical ganglion; (ShA) Sholl analysis; (TDBTN) total dendritic branch tip number; (TDL)
total dendritic length; (WT-Ox) overexpression of wild type protein

Molecular basis of dendritic arborization 269
1999, Redmond et al. 2000), ephrinB and EphB
(Hoogenraad et al. 2005), cell adhesion molecule L1
(Demyanenko et al. 1999), N-cadherins (Yu and
Malenka 2003, Zhu and Luo 2004) and seven-pass
transmembrane cadherins (Flamingo, Celsr2 and
Celsr3) (Gao et al. 2000, Shima et al. 2007) are addi-
tional important factors, which can accelerate or
inhibit dendrite growth and branching (Table 1). For
example, Notch and Celsr3 suppress growth and
branching of dendrites of cortical pyramidal neurons
(Sestan et al. 1999, Redmond et al. 2000, Shima et al.
2007). On the other hand, N-cadherin, Celsr2 and
EphrinB-EphB enhance dendritic arborization of hip-
pocampal, as well as, cortical (Celsr2) neurons (Yu and
Malenka 2003, Hoogenraad et al. 2005, Shima et al.
2007).
In addition to defining dendrite length and com-
plexity, cell surface proteins ensure proper dendrite-
axon contacts and suppress dendrite crossing (Parrish
et al. 2007). Recently, Down’s syndrome-related cell
adhesion molecule (Dscam) attracted attention due to
revealed participation in dendrite self-avoidance, a
mechanism by which dendrites of a particular neuron
avoid contact with one another, which presumably
ensures proper coverage of a dendritic field (Zhu et al.
2006, Hughes et al. 2007, Matthews et al. 2007, Soba
et al. 2007). Dscam is especially well-suited for this
job because of the enormous variability of its isoforms.
In Drosophila, the alternative splicing of Dscam may
result in over 35 000 various isoforms. Indeed, it was
shown for several types of Drosophila neurons that
neighboring dendrites expressing the same isoform of
Dscam repulse based on a homophilic Dscam isoform
interaction (Zhu et al. 2006, Hughes et al. 2007,
Matthews et al. 2007, Soba et al. 2007).
In addition to interneuronal interactions, interac-
tions between neurons and glial cells ensure proper
dendritic arborization. Yamamoto and colleagues
(2006) presented evidence that a neuro-glial interac-
tion via Neuroglian (Nrg), a member of the Ig super-
family, is important for the proper dendritic arbor
shaping of selected da neurons (ddaE) of Drosophila.
Nrg knockdown resulted in formation of ectopic den-
drites by ddaE neurons, the process that could be
reversed only by expression of Nrg in both the ddaE
neurons and the accompanying glial cells (Yamamoto
et al. 2006).
Neuronal activity is the third category of the extra-
cellular signals important for dendritic arbor develop-
ment. Neuronal transmission can either increase or
decrease dendritic arborization (for more thorough
review see McAllister 2000). A very elegant example
demonstrating the neuronal activity-dependent posi-
tive effects on dendrite growth comes from time-lapse
in vivo imaging of dendritic arbors of developing neu-
rons in the optic tectum of Xenopus laevis. Sin and
colleagues (2002) showed that dendritic arbors of the
developing tectal neurons are regulated by visual
input. A four-hour light exposure resulted in substan-
tial increases in dendrite growth dynamics and total
dendritic length. This dendritic arbor reaction to the
light was blocked by inhibition of the alpha-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
and N-methyl-D-aspartic acid (NMDA) receptor-
mediated glutamatergic transmission. Indeed, Ewald
and coworkers (2008) showed that precise subunit
composition of NMDA receptors (NMDARs) is impor-
tant for proper dendritic architecture in tectal neurons.
Furthermore, overexpression of peptides interfering
with AMPAR function led to decreased dendritic
branch lifetime and an overall decrease in dendritic
arbor complexity (Haas et al. 2006).
In addition to glutamatergic transmission, voltage-
gated calcium channels (VGCCs) play a role in den-
dritic arbor development. Numerous examples from
hippocampal, cortical and cerebellar in vitro cultures
show that depolarization of neurons by an application
of KCl leads to increased dendritic growth that can be
inhibited by nimodipine, an L-type calcium channel
blocker (Redmond et al. 2002, Yu and Malenka 2003,
Gaudilliere et al. 2004, Chen et al. 2005, Wayman et
al. 2006, Wu et al. 2007). Furthermore, the
γ-aminobutyric acid (GABA)-based transmission
increased dendritic growth of young interneurons (in
which GABA application results in neuronal depolar-
ization and consequent activation of VGCCs) (Gascon
et al. 2006). Application of a GABA-A receptor antag-
onist, bicuculline, caused decreases in dendrite length
and in the number of primary dendrites on subven-
tricular zone-derived neurons. Time-lapse imaging
experiments showed that GABA acts by stabilizing
newly formed dendritic branches. Nevertheless, there
are also reports of increased dendritic growth under
conditions of neuronal activity inhibition. It was shown
that inhibition of the glutamatergic transmission or
blockade of the VGCCs led to increased dendritic
growth in slices from ferret visual cortex (McAllister
et al. 1996, Baker et al. 1997).

270 M. Urbanska et al.
It is now widely accepted that the effects of neuronal
activity on dendritic arborization are due to elevated
cellular concentrations of calcium (for review see:
Konur and Ghosh 2005, Redmond and Ghosh 2005).
Lohman and coworkers (2002) showed that Ca
2+
-
induced Ca
2+
release (CICR), locally in dendrites, pre-
vented retraction of dendrites of the chick retinal gan-
glion neurons. Gascon and others (2006) presented
evidence that application of BAPTA-AM, a calcium
chelator, resulted in dendritic growth cone destabiliza-
tion.
But not only intracellular calcium concentration
regulates dendritic arbor development. Recent studies
showed that extracellular calcium can directly influ-
ence dendritic morphology by activating extracellular
calcium sensing receptors (CaSR) (Vizard et al. 2008).
Overexpression of a dominant negative mutant of
CaSR, in hippocampal neurons led to decreased den-
dritic arbor complexity.
INTRACELLULAR MECHANISMS
UNDERLYING DENDRITIC ARBOR
FORMATION AND STABILITY
Extracellular factors need intracellular messengers
to affect dendritic arbor development. In the second
part of this review we present recent developments in
our understanding of the molecular mechanisms under-
lying a conversion of those extracellular signals to
changes in a dendritic arbor morphology. We focus on
four crucial aspects: signal transduction, cytoskeleton
dynamics, gene expression and membrane trafficking.
Major signal transduction pathways in the
control of dendritic branching
Extracellular signals activate a myriad of intracel-
lular signaling pathways. Major players in cellular
signaling include small G-proteins of the Ras family,
protein kinases and protein phosphatases (Table II). In
what follows, we will focus on signaling proteins that
are among the most well-documented.
The Ras family of small GTPases
Small GTPases of the Ras family play a central role
in a neuronal signal transduction and are crucial for
several aspects of neuronal development, synaptic
plasticity, and learning and memory (Mazzucchelli
and Brambilla 2000, Tada and Sheng 2006). Dendritic
arbor growth is also heavily regulated by the Ras fam-
ily proteins, particularly Ras, Rap, and Rit (Table II).
Jaworski and coauthors (2005) and Kumar and others
(2005) investigated signaling pathways involved in
neurotrophic factor-dependent dendritic branching
and dendritic spine development, and showed that
increased Ras activity led to an increase in the total
number of dendrites and the overall complexity of
dendritic arbors of hippocampal neurons in culture.
Inhibition of an endogenous Ras by overexpression of
a dominant negative (DN) mutant, RasN17, blocked
dendritic growth induced by both BDNF and calcium/
calmodulin-dependent protein kinase I (CaMKI),
which is regulated by neuronal activity (Kumar et al.
2005, Wayman et al. 2006). Looking for signaling
cascade members acting downstream of Ras, Jaworski
and colleagues (2005) showed that the Ras effect on
dendritic arbor depended on phosphoinositdide-3’
kinase (PI3K), extracellular signal-regulated kinases
(ERKs), phospholipase D, and mammalian target of
rapamycin (mTOR) kinase. Ras is also important for
dendritic development in vivo as mice overproducing
a constitutively active (CA) mutant of Ras, RasV12,
had more elaborated dendritic arbors (Alpar et al.
2003). Although most of the work published so far
documents the positive effects of Ras activation on
dendritic arborization, recently Huang and others
(2007) presented evidence that overexpression of
v-KIND, a Ras guanine exchange factor (GEF) lead-
ing to Ras activation, inhibited dendritic arbor growth.
The potential of v-KIND to decrease dendritic growth
and arborization depended on its ability to bind to and
increase threonine phosphorylation of microtubule
associated protein 2 (MAP2). This behavior may sug-
gest that, under certain conditions, Ras is involved in
protein complexes that can have either permissive and
inhibitory effects on dendritic arbor development and/
or stability.
Additional members of the Ras family, Rap1, Rap2
and Rit, are involved in shaping the dendritic arbor
(Table II). Overexpression of a constitutively active
form of Rap1 (Rap1V12) in cortical neurons in vitro
increased the number of dendritic branches, especially
those in close proximity to the cell soma (Chen et al.
2005). Overexpression of Rap1N17, a dominant nega-
tive mutant of Rap1 resulted in opposite effects, both
in dissociated and organotypic neuronal preparations.
Moreover, overexpression of either Rap1N17 or

Molecular basis of dendritic arborization 271
Table II
Proteins involved in intracellular processes underlying dendritic arborization
Protein/
Protein
complex
Effect on dendrites Nervous system
structure/Species
Reference
Signal transduction
Ras CA Ox – increased complexity (ShA)
Tg – increased total dendritic tree surface
hippocampus, cortex
/rat, mouse
Jaworski et al. 2005, Kumar
et al. 2005, Alpar et al. 2003
Rap1
DN-Ox – decreased complexity; prevented
KCl-induced complexity increase
CA-Ox – increased number of proximal branches
cortex/rat Chen et al. 2005
Rap2 DN-Ox – increased TDL
CA-Ox – decreased TDL
hippocampus/rat Fu et al. 2007
Rit DN-Ox - increased TDL
CA-Ox - decreased TDL
hippocampus/rat Lein et al. 2007
CaMKI CA-Ox – increased TDL
DN-Ox – prevents KCl-induced TDL increase
KnD - prevents Bic-induced TDL increase
hippocampus/rat,
mouse
Wayman et al. 2006
CL3/CaMKIγ WT-Ox – increased TDL
KnD, KO – decreased TDL and TDBTN
cortex/rat Takemoto-Kimura et al.
2007
CaMKIIα KnD - decreased TDL cerebellum/rat Gaudilliere et al. 2004
CaMKIIβ KnD – decreased dendritic arbor perimeter hippocampus/rat Fink et al. 2003
CaMKIV CA-Ox – increased TDL, TDBTN cortex, hippocampus
/mouse, rat
Redmond et al. 2002, Yu
and Malenka 2003
ERK1/2 Inh. - prevents BDNF-induced primary
dendrites growth
cortex/rat Dijkhuizen and Ghosh 2005
JNK1 DN-Ox; KO – increased DBPN and ADL cerebellum/mouse
PI3K WT-Ox – increased TDL
DN-OX & Inh. - decreased TDBTN
CA-Ox – increased TDL, TDBTN,
complexity (ShA)
Inh. - BDNF-induced primary dendrites
growth inhibition
hippocampus, cortex
/rat
Jaworski et al. 2005, Kumar
et al. 2005, Dijkhuizen and
Ghosh 2005

272 M. Urbanska et al.
Akt DN-OX & Inb - decreased TDBTN and
dendritc arbor simplification (ShA)
CA-Ox – increased TDBTN, complexity (ShA)
hippocampus/rat Jaworski et al. 2005, Kumar
et al. 2005
mTOR KnD, Inb - decreased TDBTN and dendritic
arbor simplification (ShA)
hippocampus/rat Jaworski et al. 2005, Kumar
et al. 2005
p70S6K KnD – decreased TDBTN and dendritic arbor
simplification (ShA)
hippocampus/rat Jaworski et al. 2005
GSK3β
Inh. – increased number of dendrites, TDL and
dendritic arbor complexity (ShA)
SCG, hippocampus,
cortex/rat
Naska et al. 2006
Fyn KO – decreased DBPN cortex/rat Morita et al. 2006
Abl CA-Ox – increased number of primary
dendrites and length
Inh. – decreased number of primary and
secondary dendrites and length
hippocampus/rat Jones et al. 2004
Par1b/MARK2 WT-Ox – decreased TDL and TDBTN
KnD - increased TDL and TDBTN
hippocampus/rat Terabayashi et al. 2007
Cytoskeleton
RhoA CA-Ox – decreased number of dendritic
segments, TDBTN, dendritic arbor
simplification (ShA)
CA-Ox – decreased branch additions after
light exposure
hippocampus/rat,
optic tectum/X. laevis
Nakayama et al. 2000, Sin
et al. 2002, Yu and Malenka
2003
Rac1 DN-Ox - decreased number of primary
dendrites, decreased TDL, TDBTN
CA-Ox – increased number of primary
dendritesKO – decreased number of terminal
branches
cortex/rat,
da/D. melanogaster
Threadgill et al. 1997, Lee
et al. 2003, Rosso et al.
2005
Cdc42 DN-Ox - decreased number of primary
dendrites
CA-Ox – increased primary dendrites number
cortex/rat Threadgill et al. 1997
Tiam-1
KnD – dendritic arbor simplification (ShA)
hippocampus/rat Tolias et al. 2005
Kalirin-7 KnD – decreased TDL and dendritic arbor
simplification (ShA)
hippocampus/rat Ma et al. 2003
Lfc WT-Ox – decreased number of dendritic
segments
hippocampus/rat Ryan et al. 2005

Molecular basis of dendritic arborization 273
N-WASP WT-Ox – increased number of neurites and
DBPN
hippocampus/rat Pinyol et al. 2007
Cobl WT-Ox – increased DBPN, number of
dendrites, decreased dendrite length
KnD - decreased DBPN
hippocampus/rat Ahuja et al. 2007
Pak1 DN-Ox - decreased number of dendrites
CA-Ox – increased number of dendrites
cortex/mouse Hayashi et al. 2002
ROCK CA-Ox - decreased number of dendritic
segments
CA-Ox - decreased branch additions after
light exposure
hippocampus/rat
optic tectum/X. laevis
Nakayama et al. 2000, Sin
et al. 2002
MAP1 &
MAP2
KO – decreased length of dendrites hippocampus/mouse Teng et al. 2001
CHO1/MLKP1 KnD – increased dendrite length; dendrite
straightening
hippocampus/mouse Yu et al. 2000
CRMP3 KO – decreased DBPN and TDL hippocampus/mouse Quach et al. 2008
Lis1 KO – decreased total number of segments mushroom body
/D. melanogaster
Liu et al. 2000
Kakapo KO – reduced lateral branches
md/D. melanogaster
Prokop et al. 1998, Gao et
al. 1999
Septin-7 WT-Ox – increased TDBTN and complexity
(ShA)
KnD – decreased TDBTN and complexity (ShA)
hippocampus/rat Tada et al. 2007, Xie et al.
2007
Transcription, mRNA transport, translation
BAF53 KO - decreased number of dendrites and TDL hippocampus, cortex,
cerebellum/mouse
Wu et al. 2007
CREST KO – decreased TDL (hippocampus, cortex)
and DBPN (cortex)
cortex, hippocampus
/rat
Aizawa et al. 2004
MECP2 WT-Ox - dendritic arbor simplification (ShA)
KnD – dendritic arbor simplification (ShA)
hippocampus/rat Zhou et al. 2006
CBP Inh - decreased TDL and KCl-induced growth cortex/rat Redmond et al. 2002
CREB CA-Ox – increased TDL
DN-Ox – decreased complexity, KCl-induced
growth inhibition,
KnD - KCl-induced growth inhibition
cortex, hippocampus
/rat
Redmond et al. 2002,
Wayman et al. 2006

274 M. Urbanska et al.
NeuroD KnD - decreased TDL and KCl-induced
growth inhibition
cerebellum/rat Gaudilliere et al. 2004
c-Fos KO – cocaine induced TDBTN increase
inhibition
nucleus accumbens,
caudate putamen/
mouse
Zhang et al. 2006
Pumilio WT-Ox – decreased number of higher order
branches
KO – higher order branch number reduction
of class IV da neurons
da/D. melanogaster
Ye et al. 2004
Nanos WT-Ox - decreased number of higher order
branches
KO – higher order branch number reduction
of class IV da neurons
da/D. melanogaster
Ye et al. 2004
FMR1 WT-Ox – decreased number of dendritic ends
per 1000 μm2
KO - increased number of dendritic ends per
1000 µm2
da/D. melanogaster
Lee et al. 2003
Me31B WT-Ox – decreased number of higher order
branches
KO – increased number of higher order
branches
da/D. melanogaster
Barbee et al. 2007
4E-BP1 WT, CA-Ox – decreased TDBTN and
complexity (ShA)
hippocampus/rat Jaworski et al. 2005
Membrane turnover
Protein kinase
D
DN-Ox – decreased TDL, TDBTN and
complexity (ShA)
hippocampus, cortex
/rat
Horton et al. 2005
GRASP65 WT-Ox – disruption of polarized dendrite
growth
hippocampus/rat Horton et al. 2005
SNAP-25 Botulinum neurotoxin A application –
decreased TDL
hippocampus/mouse Grosse et al. 1999
TI-VAMP WT-Ox – decreased dendrites length and
number
hippocampus/rat Martinez-Acra et al. 1999
Sar1 KO – decreased TDL
KnD - decreased TDL
da/D. melanogaster
hippocampus/rat
Ye et al. 2007
(ADL) average dendrite length; (Bic) bicucculline; (CA-Ox) overexpression of constitutively active mutant; (DBPN)
number of branching points; (DN-Ox) overexpression of dominant negative mutant; (Inh) non genetic inhibition; (KO)
knockout; (Knd) knockdown; (SCG) superior cervical ganglion; (ShA) Sholl analysis; (Tg) transgenic animal; (TDBTN)
total dendritic branch tip number; (TDL) total dendritic length; (WT-Ox) overexpression of wild type protein

Molecular basis of dendritic arborization 275
Rap1GAP (a GTPase-activating protein for Rap1, a
natural inhibitor of Rap1 activity) blocked induction
of dendritic arbor growth caused by activation of
voltage-gated calcium channels (Chen et al. 2005). In
terms of downstream cellular mechanisms, more
detailed analyses suggest that Rap1 acts via ERK
kinases and activation of CREB-dependent transcrip-
tion (Chen et al. 2005). Work by Ghosh group, per-
formed on neurons transfected at relatively early
stages of development, led to a conclusion that Rap1 is
permissive for dendritic growth. Opposite results
were obtained by Fu and coauthors (2007) in a study
of the role of Rap1 and Rap2 in more mature (DIV10-15)
hippocampal neurons. Overexpression of the Rap1-
DN mutant resulted in increased total dendritic length
(Fu et al. 2007). Moreover, in more mature neurons,
overexpression of Rap2V12 resulted in a substantial
decrease in the total length of dendritic branches due
to dendrite retraction (Fu et al. 2007). On the other
hand, overexpression of Rap2-DN as well as Rap1-DN
increased total dendrite length. The authors concluded
that, in mature neurons, Rap2 restricts dendritic
growth (Fu et al. 2007). Taken together, the data sug-
gest that Rap proteins can act differently during devel-
opment to stabilize the dendritic arbor. Apart from
Ras and Rap, Rit, another member of the Ras family,
influences dendritic growth. Its activation in hip-
pocampal and sympathetic neurons promotes dendrite
growth (Lein et al. 2007).
Protein kinases
All major protein kinases known to be active in
neurons influence dendritic arbor development
(Table II). These enzymes include CaMK (Wu and
Cline 1998, Redmond et al. 2002, Fink et al. 2003,
Yu and Malenka 2003, Gaudilliere et al. 2004,
Wayman et al. 2006, Hoogenraad et al. 2007,
Takemoto-Kimura et al. 2007), mitogen-activated
protein kinases (MAPK) (Bjorkblom et al. 2005,
Dijkhuizen and Ghosh 2005), protein kinase A
(PKA) (Leemhuis et al. 2004), PI3K (Dijkhuizen and
Ghosh 2005, Jaworski et al. 2005, Kumar et al.
2005), mTOR (Jaworski et al. 2005, Kumar et al.
2005, Brandt et al. 2007, Jossin and Goffinet 2007),
glycogen synthase kinase 3 beta (GSK3β) (Naska et
al. 2006), and non-receptor (Fyn, Abl) (Jones et al.
2004, Morita et al. 2006) and receptor tyrosine
kinases (TrkB) (Yacoubian and Lo 2000).
CaMK
CaMKs are serine/threonine protein kinases, pri-
marily regulated by the Ca
2+
/calmodulin complex, that
have many functions in neuronal morphogenesis and
plasticity. In 1998, Wu and Cline, presented evidence
that, in developing tectal neurons of X. laevis, CaMKII
is expressed only in more mature neurons with elabo-
rated and stable dendritic arbors in vivo (Wu and Cline
1998). Younger neurons, characterized by very dynam-
ic dendritic growth, high rates of dendritic branch
additions and retractions, did not express that enzyme.
Consequently, overexpression of CaMKII in the young-
er neurons led to premature stabilization of the den-
dritic arbors (longer branch life time) and a lower net
increase of total dendritic length. Application of a
CaMK inhibitor, KN93, resulted in increased dynam-
ics of dendritic arbor of neurons already expressing
CaMKII and having established complex dendritic
arbors (Wu and Cline 1998). CaMKII was shown to
control processes of dendritic arbor growth in several
different ways. Gaudilliere and others (2004) showed
that CaMKIIα controls neuronal activity-dependent
growth of dendrites of cerebellar neurons by phospho-
rylation of NeuroD at S336. Fink and colleagues (2003)
revealed that CaMKII is important for dendritic
arborization of hippocampal neurons; however, their
results point to CaMKIIβ as a major regulator of this
process. Only overexpressed wild-type CaMKIIβ was
able to bind to and regulate the actin cytoskeleton and 
increase dendritic arborization. Finally, Hoogenraad
and coworkers (2007) showed that CaMKII controls
dendritic arborization through degradation of liprin1,
a protein critical for cellular localization and activity
of a tyrosine phosphatase LAR1.
In addition to CaMKII, CaMKIV and CaMKI were
shown to control dendritic growth and arborization
induced by either BDNF or neuronal activity (Redmond
et al. 2002, Yu and Malenka 2003, Wayman et al.
2006, Takemoto-Kimura et al. 2007). Both CaMKs
control dendritic arbor growth at a transcriptional level
(Redmond et al. 2002, Wayman et al. 2006) (see
below). Yu and Malenka (2003) additionally showed
that CaMKIV required N-cadherin and non-nuclear
functions of β-catenin to promote dendritic arbor
growth. Recently, Takemoto-Kimura and colleagues
(2007) presented evidence that the membrane-anchored
neuronal CLICK-III(CL3)/CaMKIγ promoted BDNF-
induced dendrite extension of young (1–3 days in vitro)

276 M. Urbanska et al.
cortical neurons, by acting upstream of SIF and Tiam
1-like exchange factor (STEF), a Rac1 GEF. CL3
knockdown using RNAi led to decreased length and
number of dendrites of both BDNF-treated and control
cells, probably due to downregulation of Rac1 activity
and changes in the actin cytoskeleton (Takemoto-
Kimura et al. 2007).
Class I PI3K
Recently several reports addressing the role of PI3K
in dendritic arbor development have been published.
Class I PI3K is a lipid kinase that phosphorylates phos-
phatidylinositol 4,5-bisphosphate (PIP2) to phosphati-
dylinositol 3,4,5-trisphosphate (PIP3). Increased levels
of PIP3 results in activation of several PI3K effectors,
including Akt kinase, several GEFs and GAPs for
small GTPases (RhoA, Rac1 and Arf6) (Rodgers and
Theibert 2002). Jaworski and others (2005) and Kumar
and colleagues (2005) showed that overexpression of a
constitutively active form of PI3K led to increased
dendritic arbor complexity and expansion of dendritic
fields of hippocampal neurons in vitro. Inhibition of
PI3K activity, either genetically or pharmacologically,
had opposite effects (Jaworski et al. 2005, Kumar et al.
2005). Dijkhuizen and Ghosh (2005) used preparations
of cortical neurons and showed that PI3K, along with
ERK and phospolipase Cg1, are crucial for BDNF-
induced growth of primary dendrites. Moreover, over-
expression of PI3K-CA alone was sufficient to induce
growth of primary dendrites (Dijkhuizen and Ghosh
2005). Leemhuis and coworkers (2004) studied the
effects of PI3K inhibition by wortmanin on the dynam-
ics of dendritic arbor growth of hippocampal neurons
in in vitro culture. Time-lapse microscopy, over a
period of 8 h, revealed that PI3K inhibition completely
abolished retractions of existing branches and decreased
additions of new branches by 50%.
Molecular mechanisms downstream of PI3K,
involved in dendritic arbor development and stability,
are diverse and involve both de novo protein synthesis
and the regulation of actin cytoskeleton dynamics.
Work by Jaworski and coauthors (2005) and Kumar
and others (2005) showed that a constitutively active
Akt mutant mimicked the dendritic branching effects
of increased PI3K activity. Both, PI3K-CA- and Akt-
CA-dependent dendritic branching were blocked by
inhibition of mTOR kinase. mTOR kinase is a well
known regulator of protein synthesis via its down-
stream targets p70S6 kinase (p70S6K) and eIF-4E
binding protein 1 (4E-BP1) (Burnett et al. 1998).
Importantly, knockdown of p70S6K by means of
RNAi, like mTOR knockdown, led to a severe simpli-
fication of dendritic arbors in hippocampal neurons
(Jaworski et al. 2005). Overexpression of a constitu-
tively active form of 4E-BP1 (activity of which could
not be turned off by the PI3K-Akt-mTOR pathway)
completely blocked dendritic growth and arborization
induced by PI3K-CA (Jaworski et al. 2005). These
results suggest that, at certain stages of dendritic arbor
development PI3K regulates this process by control-
ling protein translation.
Nevertheless, the effects of PI3K on the dendritic
arbor cannot be solely attributed to protein synthesis.
Dijkhuizen and Ghosh (2005) showed that BDNF-
induced growth of primary dendrites is insensitive to
cycloheximide, a general protein translation inhibitor.
PI3K can also regulate actin cytoskeleton dynamics by
enhancing Rac1 activity, probably via recruitment of
PI3K to the Rac1-activating molecular complex Eps8–
Abi1–Sos-1 (Innocenti et al. 2003). But it is important
to stress that overexpression of Abi-1 results in a
decrease, and its knock down by RNAi in an increase,
of dendritic arbor complexity of hippocampal neurons
(Proepper et al. 2007). That suggests a more complex
role of Abi-1 during dendritic arbor development,
potentially due to additional nuclear functions of this
protein. Another possibility is that PI3K can exert
positive effects on dendritic growth by suppressing
inhibitory effects of RhoA on branch formation and
extension (Leemhuis et al. 2004) (see also below).
Protein kinases regulating MAP2 phosphorylation
Although particular kinases regulate dendritic arbor
growth influencing several cellular processes, various
protein kinases may also converge on a common
downstream effector protein. MAP2, a protein marker
for dendrites, can serve as a good example. MAP2 is a
microtubule-stabilizing protein; its phosphorylation by
different kinases can exert opposite effects on den-
dritic arborization. For example, phosphorylation of
MAP2 in a C-terminal proline-rich region by c-Jun
N-terminal kinase 1 (JNK1) contributes positively to
dendrite elongation (Bjorkblom et al. 2005). Lack of
JNK1 in cerebellar granular neurons results in dephos-
phorylation of MAP2, shortening of dendrites, and
increased dendritic branching. Coexpression of a JNK

Molecular basis of dendritic arborization 277
activator, δMEKK1, with MAP2 resulted in elongation
of dendrites.
Another kinase capable of phosphorylating MAP2
is Polarity-regulating kinase partitioning defective 1/
Microtubule affinity-regulating kinase 2 (Par1b/
MARK2) (Terabayashi et al. 2007). Overexpression of
this kinase, leading to phosphorylation of a KXGS
motif in MAP2, had opposite effects on hippocampal
neuron dendritic arbor development, causing a decrease
of total dendritc length and dendritic branching.
Knockdown of Par1b/MARK2 by RNAi increased
both dendritic length and branching.
Role of actin and microtubule cytoskeleton in
dendritic arbor development and stabilization
A very tight control of actin and microtubule
cytoskeleton organization is indispensable for the for-
mation of proper cell morphology (Table II). The best
known regulators in this context are RhoA, Rac1,
Cdc42 (cell division cycle 42), regulators of cytoskel-
eton dynamics that belong to the Rho family of small
GTPases (Burridge and Wennerberg 2004, Jaffe and
Hall 2005).
In most studies published thus far, increased activity
of RhoA and inhibition of Rac1 or Cdc42 resulted in
significant simplification of the dendritic trees in
many neuron types (Threadgill et al. 1997, Nakayama
et al. 2000, Hayashi et al. 2002). In contrast, activation
of Rac1 or Cdc42 caused an increase in the number of
dendrite branches (Threadgill et al. 1997, Nakayama et
al. 2000, Hayashi et al. 2002).
Several extracellular signals are involved in the
regulation of the Rho GTPases during dendritic arbor
formation. Li and coauthors (2002), developed a meth-
od for the detection of Rho GTPase activity in situ in
the optic tectum of Xenopus and showed that electrical
stimulation of an optic nerve led to increased activity
of Rac1 and decreased activity of RhoA, in an
NMDAR- and AMPAR-dependent manner. Studies by
Sin and colleagues (2002), indicated that accelerated
dendritic arbor development of the Xenopus optic tec-
tum neurons induced by 4h light exposure depended
on the Rho GTPases. Overexpression of RhoA-CA in
tectal neurons blocked light-induced development, as
did a genetic decrease of Rac1 and Cdc42 activity.
Inhibition of RhoA occluded the effect of light on den-
dritic arbor growth. Li and coworkers (2002) also pre-
sented evidence for an extensive cross-talk between
the Rho GTPases during dendritic branching. For
example, activation of RhoA blocked dendritic growth
induced by Rac1-CA overexpression. In addition to
electrical and neurotransmitter stimuli, other extracel-
lular signals such as BDNF, Wnt-7 and EphrinB-EphB
interaction, control dendritic growth employing the
Rho GTPases (Penzes et al. 2003, Rosso et al. 2005,
Takemoto-Kimura et al. 2007).
Guanine nucleotide exchange factors and GTPase-
activating proteins for Rho GTPases
How is the activity of Rho GTPases regulated dur-
ing dendritogenesis? Small GTPases cycle between an
active (GTP-bound) and an inactive (GDP-bound)
states (for review see Etienne-Manneville and Hall
2002). In the GTP-bound form, active GTPases bind to
and regulate the activity of several downstream effec-
tors. Activation of small GTPases depends on the bal-
ance between guanine nucleotide exchange factors
(GEFs) and GTPase-activating proteins (GAPs), which
is regulated by extracellular signals important for den-
dritic arbor development and stabilization.
Some mammalian Rac1 GEFs, such as Tiam-1 and
Kalirin-7, interact with glutamate receptors or/and
postsynaptic density proteins involved in glutamate
receptor anchoring and turnover, linking glutamater-
gic neurotransmission to Rac1 activation. Both
Kalirin-7 and Tiam-1 were shown to be necessary for
NMDA-induced Rac1 activation (Tolias et al. 2005,
Xie et al. 2007b). Kalirin-7 is a multidomain protein
that interacts with multiple Rho proteins, and is pre-
dominantly expressed in the brain, localizing to den-
dritic spines where it was shown to interact with sev-
eral postsynaptic density scaffold proteins including
PSD-95 (Penzes et al. 2000, 2001). RNAi-mediated
knockdown of Kalirin-7 led to a simplification of hip-
pocampal neuron dendrites in both dissociated and
organotypic cultures (Ma et al. 2003). Tiam-1, like
Kalirin-7, is widely expressed in the brain and local-
izes to dendritic spines where it interacts with the
NMDA receptor subunit NR1 (Tolias et al. 2005).
Transfection of hippocampal neurons with siRNA
against Tiam-1 resulted in decreased dendritic com-
plexity. BDNF regulates Rac1 activity, recruiting
GEFs. Recently, Rac1 GEF, SIF and Tiam 1-like
exchange factor (STEF), has been described to act
downstream of BDNF and CLICK-III(CL3)/CaMKIγ
during dendritic growth (see above). For example,

278 M. Urbanska et al.
application of either a dominant interfering fragment
(PHnTSS) of STEF or Rac1-DN blocked the positive
effect of CL3 overexpression on dendrite length
(Takemoto-Kimura et al. 2007). Lee and colleagues
(2003) revealed that Rac1 protein levels can be con-
trolled during dendritic arbor development by transla-
tional inhibition by Drosophila Fragile X-related pro-
tein (FMR1). mRNA encoding Rac1 was found in
FMR1-containing ribonucleoprotein particles (RNPs,
see also below) and overexpression of Rac1 partially
rescued detrimental effects of FMR1 overexpression
on the da neurons dendritic arbor complexity (Lee et
al. 2003). All of these observations show that both the
expression level and activity of Rac1 are under strict
and local control in dendrites.
Rho GEFs also regulate dendritic arbor growth. Lfc
is a Rho-GEF abundantly expressed in the brain that
localizes to dendrites (Ryan et al. 2005). Lfc redistrib-
utes from a dendritic shaft to dendritic spines upon
NMDAR and VGCC stimulation, and Ca
2+
influx into
cells. Consistent with the role of activated RhoA in
dendritic growth, long-term overexpression of Lfc in
hippocampal neurons in vitro caused a significant
decrease of the number of dendritic segments, in a
Rho-GEF activity-dependent manner (Ryan et al.
2005). Certain signaling pathways impinge their effects
on dendritic arbor growth by inhibiting RhoA activity.
For example, Abl, a non-receptor tyrosine kinase,
stimulates extension and branching of dendrites via
inhibition of RhoA. Inhibition of Abl kinase leads to
increased RhoA activity and significant simplification
of dendritic arbors in hippocampal neurons (Jones et
al. 2004). On the other hand, Abl-CA expression
results in new dendrite formation and branching,
which can be suppressed by RhoA-CA (Jones et al.
2004).
Regulation of the actin cytoskeleton during
dendritic arborization is dependent on Rho
GTPases
The Rho GTPases are regulators of actin polymer-
ization rates and spatial organization (Etienne-
Manneville and Hall 2002, Burridge and Wennerberg
2004, Jaffe and Hall 2005). In eukaryotic cells, down-
stream effectors of the Rho GTPases, Arp2/3 and
mDia, are two major factors involved in actin polym-
erization. The activity of cofilin, an actin severing
factor which increases the number of uncapped, barbed
ends, can promote both filament assembly and disas-
sembly.
Rac1 and cdc42 activate Arp2/3 (and consequently
actin polymerization) indirectly via Wiskott-Aldrich
syndrome (WASP) family proteins, WAVE and
N-WASP, respectively, leading to formation of a
branched filament network (for review see Etienne-
Manneville and Hall 2002, Burridge and Wennerberg
2004, Jaffe and Hall 2005). Both N-WASP and Arp2/3
play important roles in the proper shaping of the den-
dritic arbor (Pinyol et al. 2007, Rocca et al. 2008).
Overexpression of N-WASP increased the number of
neurites and branch points in developing hippocampal
neurons in vitro; these effects depended on cdc42
activity (Pinyol et al. 2007). Recently, Rocca and coau-
thors (2008) showed that Arp2/3 actin nucleation
activity is important for proper dendritic branching
patterns in developing hippocampal neurons. A synap-
tic protein that binds Arp2/3, PICK1, disrupts Arp2/3
binding to N-WASP and inhibits Arp2/3-mediated
actin polymerization. PICK-1 knockdown caused
increases in proximal dendrite branching and decreas-
es in distal arborization. The effects of the PICK-1
knockdown were reversed by overexpression of PICK-1
resistant to siRNA. Taken together, these data empha-
size the importance of actin nucleation for proper den-
dritic arborization.
RhoA regulates actin polimerization, directly bind-
ing a formin, mDia, and inducing the linear elongation
of actin filaments. A role for this formin has not been
studied in the context of dendritic development, but
mDia activation via RhoA was found important for
neurite elongation in PC12 cells upon NGF exposure
(Nusser et al. 2006).
Recently, Cordon-Bleu (Cobl) protein was identified
as a new actin nucleation factor enriched in the brain
(Ahuja et al. 2007), which acts independently from the
Arp2/3 complex. Cobl promotes formation of long,
unbundled and unbranched filaments, gives rise to
plus-end (barbed–end) growth and localizes to sites of
high actin dynamics. In primary hippocampal neurons,
overexpression of the Cobl C-terminal domain, con-
taining all WASP homology 2 domains necessary for
its activity, induced formation of highly branched den-
dritic arbors built of short dendrites whereas RNAi-
mediated knockdown of Cobl resulted in a significant
reduction in the length and branching of dendrites.
The Rho GTPases also influence the dendritic
arborization activating proteins that are not directly

Molecular basis of dendritic arborization 279
involved in actin nucleation. p21-activated
kinase
(Pak1) acts downstream of Rac1, and through effector
proteins, such as filamin or LIM kinase (LIMK), to
stabilize actin filaments. A constitutively active form
of Pak1, when expressed in immature cortical neurons,
increased the number of apical and basal dendrites.
Disruption of endogenous Pak1 activity by a dominant
negative mutant had an opposite effect (Hayashi et al.
2002). In cultures of hippocampal neurons, either
hyperactivation or loss of Pak1 lead to disruption of
neuronal
morphology and neurite differentiation to an
axon and dendrites (Jacobs et al. 2007).
Rho kinase (ROCK) is a downstream target for
RhoA. Activation of ROCK has complex cellular con-
sequences, including a myosin contraction of actin
filaments and an activation of LIMK. Overexpression
of ROCK-CA (ROCK∆3), in rat hippocampal neurons
in organotypic culture, caused simplification of den-
dritic trees (Nakayama et al. 2000). Consequently,
inhibition of ROCK by a specific inhibitor, Y-27632,
prevented dendritic arbor simplification caused by
RhoA-CA overexpression or by suppression of Abl
kinase which leads to RhoA activation (Nakayama et
al. 2000, Jones et al. 2004). Overexpression of ROCK-
CA in vivo in the Xenopus optic tectum neurons pre-
vented changes in dendritic arbor triggered by light
exposure (Sin et al. 2002; see also above).
Microtubule cytoskeleton
Besides involvement in the control of actin cytoskel-
eton, Rho GTPases regulate microtubule dynamics
and interactions of actin and microtubules (for review
see Jaffe and Hall 2005). Rac1 stabilizes microtubules
via JNK1-dependent phosphorylation of MAP2 (see
above). RhoA alters the microtubule cytoskeleton by
decreasing levels of cypin (Chen and Firestein 2007).
Since, cypin binds to tubulin heterodimers and pro-
motes the assembly of microtubules (Akum et al.
2004), a decreased cypin levels, resulting from RhoA
activation, results in a decreased dendrite number
(Chen and Firestein 2007). The development and sta-
bility of a proper dendritic arbor morphology depend
on several, non-Rho GTPase-related microtubule
binding proteins, including MAPs, microtubule plus-
end tracking proteins, and motor proteins. CHO1/
MKLP1, CRMP3, Lis1, MAP1b, kakapo are a few
examples (Prokop et al. 1998, Liu et al. 2000, Yu et al.
2000, Teng et al. 2001; Quach et al. 2008).
Septins
Septins are another cytoskeletal component identi-
fied to play a role in dendritic branching. They are
evolutionary conserved proteins with essential func-
tions in cytokinesis, membrane trafficking, and scaf-
folding for the assembly of cellular factors (Kinoshita
2006). In the rat brain, expression patterns of members
of the septin family are cell-type specific and change
during development (Tada et al. 2007). Overexpression
of neuron specific isoforms, Septin2, Septin6 or
Septin7 increase dendritic arbor complexity (Tada et
al. 2007, Xie et al. 2007a), and RNAi-mediated knock-
down reduces dendritic branching. In cultured hip-
pocampal neurons, Septin7 is localized at dendritic
branch points and at the base of dendritic protrusions
(Tada et al. 2007).
Transcription and translation
Transcription
Transcription plays an important part in intrinsi-
cally driven genetic program-based dendritic
arborization (see above). Nevertheless, in mammali-
an neurons, transcription factors, cofactors and chro-
matin-modifying proteins are studied mostly in the
context of dendrite development induced by extracel-
lular factors. A general necessity for transcription
during neuronal activity-dependent dendritic arbor
growth is well-exemplified in the recent work of Wu
and others (2007) on chromatin remodeling com-
plexes in neurons. They showed that BAF53b is
a crucial protein for ATP-dependent remodeling of
chromatin, a process that makes promoters of certain
genes accessible to transcriptional machinery.
Hippocampal neuronal cultures derived from mice
lacking BAF53b had deficits in KCl-induced den-
dritic arbor growth. BAF53b acts in concert with
transcriptional coactivator CREST, which was previ-
ously identified as a calcium-responsive transcription
coactivator important for neuronal activity-induced
dendritic arbor growth in hippocampal and cortical
neurons (Aizawa et al. 2004).
Methyl-CpG-binding protein 2 (MECP2) is a pro-
tein that binds to methylated DNA and functions as
a transcription repressor. Overexpression of MECP2 in
organotypic hippocampal cultures, as well as knock-
down of MECP2 by RNAi, resulted in simplification

280 M. Urbanska et al.
of the dendritic arbor (Zhou et al. 2006). These find-
ings suggest that proper neuronal development requires
a very precise set point for MECP2 expression. Indeed,
overexpression of an siRNA-resistant form of MECP2
that could be phosphorylated by CaMKII reversed the
detrimental effects of RNAi.
CREB-binding protein (CBP) is another general
chromatin modifier and transcription coactivator shown
to play a pivotal role in dendritic arborization.
Overexpression of a mutant form of adenoviral E1A
protein, which inhibits CBP, blocked CaMKIV-
dependent and KCl-induced dendritic growth of corti-
cal neurons in vitro (Redmond et al. 2002). CBP is
c r u c i a l f o r C R E B t r a n s c r i p t i o n a l a c t i v i t y . O v e r e x p r e s s i o n
of various forms of dominant negative mutants of
CREB or siRNA also prevented KCl-, CaMKIV- and
CaMKI-induced dendritic growth in cortical and hip-
pocampal neurons (Redmond et al. 2002, Wayman et
al. 2006). Overexpression of a constitutively active
CREB mutant was sufficient to increase total dendritic
length (Wayman et al. 2006).
Other transcription factors control neuronal activity-
driven dendritic arbor growth. Gaudilliere and col-
leagues (2004) showed that removal of NeuroD by
RNAi from cerebellar granular neurons inhibited den-
dritic growth induced by both neuronal activity (KCl,
biccuculine) and CaMKIIα. c-Fos, a product of an
immediate early gene c-fos, is a TF induced by expo-
sure of animals to cocaine (Zhang et al. 2006). One of
the morphological effects of repeated cocaine adminis-
trations is increased dendritic branching of the caudate
putamen and the nucleus accumbens neurons (Zhang et
al. 2006). This particular morphological change is
missing in c-fos knockout mice, demonstrating the role
for transcription in neuronal plasticity-dependent den-
dritic arbor remodeling in vivo (Zhang et al. 2006).
Although the participation of TFs in dendritic arbor
growth is well-documented, only a few downstream
genes important for dendritogenesis have been identi-
fied. Recent examination of BAF53b target genes by a
chromatin precipitation method revealed several genes
important for neurite outgrowth. In neurons from
BAF53b knockout mice, transcription of ephexin-1,
GAP43, Stathmin, Gelsolin and Rap1A were down-
regulated while RacGAP1 was upregulated (Wu et al.
2007). More detailed analysis revealed that overex-
pression of ephexin-1 in neurons lacking BAF53b
restored responsiveness of the dendritic arbor to depo-
larization (Wu et al. 2007).
Wnt-2, expression of which depends on CREB, is
another important gene for activity-driven dendritic
growth (Wayman et al. 2006). Overexpression of
Wnt-2 in neurons in organotypic cultures is sufficient
to increase both total dendritic length and number of
branches. On the other hand, expression of Wnt antag-
onist, Wif, led to inhibition of KCl-, bicuculline- and
CaMKI-induced dendritic growth.
Lastly, analysis of target genes for the Drosophila
transcription factor Knot/Collier revealed a gene
encoding a microtubule severing protein, Spastin
(Jinushi-Nakao et al. 2007). In the class IV da sensory
neurons of Drosophila, overexpression of Knot/Collier
increased expression of Spastin and promoted dendrite
arborization that was inhibited by knockdown of
Spastin (Jinushi-Nakao et al. 2007).
mRNA dendritic transport and local protein
translation
Given that transcription is crucial for dendritic
arbor growth, protein translation must be also involved.
We already mentioned the importance of mTOR,
p70S6K, and 4E-BP1 in the translational control of
dendritic branching (Jaworski et al. 2005). Moreover,
recently Chihara et al. (2007) defined a crucial role of
protein translation in proper dendritic arborization of
the Drosophila olfactory projection neurons and the
mushroom body γ neurons. This was done by knock-
ing down genes encoding various aminoacyl-tRNA
synthetases, enzymes catalyzing attachment of amino-
acids to their corresponding tRNAs, which is indis-
pensible for translation.
The discovery of the requirement for protein trans-
lation in dendritic arbor development raises questions
about the specific locations of protein translation in
neuronal cells. It is worth stressing that translation in
neurons can take place at various locations and there-
fore can be divided to general and local (Kindler et al.
2005, Skup et al. 2008, this issue). The latter one
occurs at several discrete locations along dendrites, in
proximity to synapses and in the growth cones of
axons, and is independent from the general translation
in the cell soma (Kindler et al. 2005, Skup et al. 2008,
this issue). mRNAs transported to dendrites and
axons as ribonucleoprotein particles and their transla-
tion are activated by extracellular signals such as
BDNF or specific patterns of neuronal activity (Kindler
et al. 2005). mTOR, p70S6K and 4E-BP1 were shown

Molecular basis of dendritic arborization 281
to control translation locally in dendrites and axons
during long-lasting long-term potentiation (L-LTP)
and axon guidance, respectively (for review see:
Jaworski and Sheng 2006, Swiech et al. 2008), but
direct evidence is missing for local translation in the
process of dendritic arbor development. Nevertheless,
several indirect findings suggest such a possibility.
There is compelling evidence from Drosophila
models that translational repressors that are compo-
nents of dendritic RNPs such as Pumilio, Nanos,
FMR1 and Me31B regulate proper dendrite growth
(Lee et al. 2003, Ye et al. 2004, Barbee et al. 2006).
Overexpression of Pumilio, Nanos, FMR1 and Me31B
in the class IV da sensory neurons, reduces higher
order dendrite complexity (Lee et al. 2003, Ye et al.
2004, Barbee et al. 2006). Overexpression of RNP-
related translation repressors has consistent inhibitory
effects on dendritic branching, but knockdown of
those proteins led to diverse effects on dendritic
arbors. Inhibition of Nanos and Pumilio resulted in
reduced higher order branches in the class IV da neu-
rons and incomplete coverage of epidermis by the
dendritic arbors by 15% and 20% in neurons lacking
Nanos and Pumilio, respectively (Ye et al. 2004).
Knockdown of fmr1 increased the number of higher
order branches (Lee et al. 2003). Inhibition of Me31B,
by RNAi, substantially increased higher order branch
complexity similarly to effects of fmr1 knockdown
(Barbee et al. 2006). Nevertheless, the more branched
dendritic arbors of class IV da neurons showed incom-
plete dendritic field coverage as in the case of remov-
ing Nanos and Pumilio (Barbee et al. 2006). There are
several unclear issues remaining: (i) where do the dif-
ferences in observed phenotypes arise from, (ii) why
do dendritic arbor phenotypes of different classes of
the da neurons vary substantially in response to the
same genetic manipulations, and (iii) how does the
morphology of mammalian neurons depend on RNP
components? The role for local protein synthesis in
mammalian neurons is supported by several lines of
evidence, including those discussed above. Some
experiments designed to identify dendritic mRNAs
showed that several proteins important for control of
dendritic branching, for example CaMKIIα, glutamate
receptor subunits, BDNF, TrkB, GRIP1 and PSD95,
are translated locally in dendrites, often in a neu-
rotrophic factor-, neuronal activity- and mTOR-depen-
dent fashion (see review by Swiech et al., 2008, for
more detailed discussion).
Organellar protein translation may also contribute
to dendritic arbor development and stability. Chihara
and coauthors (2007) showed subtle differences
between the effect of translation taking place in cyto-
plasm and mitochondria on dendritic arbor. They took
advantage of the existence of cytoplasmic- and mito-
chondria-specific isoforms of several aminoacyl-tRNA
synthetases (see above). When genes encoding the
cytoplasmic forms of either tryptophanyl-tRNA syn-
thetase or glutaminyl-tRNA-synthetsase were knocked
down in the Drosophila olfactory projection neurons
or the mushroom body γ neurons, dendritic and axonal
terminal arborization was impaired (Chihara et al.
2007). When mitochondrial protein synthesis was
impaired by removal of the gene encoding mitochon-
drial ribosomal protein S12, dendrites of DL1 projec-
tion neurons reached their target (DL1 glomerulus) but
dendritic density was decreased and this effect was
increasing with age. Based on these data, Chihara and
others (2007) concluded that cytoplasmic protein
translation is crucial for dendritic arbor development,
and the mitochondrial protein translation controls the
stability of mature dendrites.
Membrane trafficking
Extensive dendritic growth during development
requires constant additions of membrane to the cell
surface. Moreover, activity-dependent branching
depends on the presence and activity of neurotransmit-
ter receptors that need to be delivered to and removed
from the cell surface. Quite surprisingly, membrane
trafficking only recently took a central stage in
research directed at understanding dendritic arboriza-
tion mechanisms. Dendrites are endowed with mem-
branous organelles, including both rough and smooth
endoplasmic reticulum (ER), the ER–Golgi intermedi-
ate compartment, and Golgi outposts that have no
membranous connections with the somatic Golgi.
Golgi outposts presumably serve both general and spe-
cific local trafficking needs, and could mediate mem-
brane trafficking required for polarized dendritic
growth during neuronal differentiation (Horton and
Ehlers 2003, Horton et al. 2005). Disruption of the
Golgi apparatus by GRASP65 overexpression (Barr et
al. 1997) abolishes the asymmetry in Golgi orientation
observed during dendritic growth, which results in a
marked reduction in dendritic polarity. Moreover,
selectively blocking Golgi outpost trafficking halts

282 M. Urbanska et al.
dendrite growth in developing neurons and causes
shrinkage of dendrites in mature pyramidal neurons
(Liljedahl et al. 2001, Horton et al. 2005).
Recent findings suggest that dendritic growth heav-
ily relies on classical exocytic traffic. Membrane pro-
teins and secretory cargo are targeted to the ER of the
exocytic pathway extending from the soma, and are
then routed to the cell surface through multiple rounds
of vesicle budding and fusion. These processes are
mediated by an evolutionarily conserved set of coat
proteins such as the SNARE complex (soluble
N-ethylmaleimide sensitive factor (NSF), SNAP-25,
syntaxins, TI-VAMP, etc.) (Cai et al. 2007, Tang 2008)
and the Rab family GTPases (Bonifacino and
Lippincott-Schwartz 2003). There is evidence for Rab8
(Huber et al. 1995), SNAP-25 (Grosse et al. 1999),
TI-VAMP (Martinez-Arca et al. 2001) and the SNARE
complex (Vega and Hsu 2001) being involved in exo-
cytosis-mediated dendritic extension. Moreover, Jan
and colleagues (Ye et al. 2007) isolated Drosophila
mutants with defects in dendritic, but not axonal,
growth in a genetic screen. Isolated mutations were
present in genes encoding Drosophila homologues of
Sec23, Sar1 and Rab1, all of which function in the early
secretory pathway, (ie, in ER–Golgi transport).
Another way whereby membrane materials can be
incorporated into the cell surface is through the recy-
cling of internalized proteins via recycling endosomes
(Maxfield and McGraw 2004, van Ijzendoorn 2006).
The requirement of Rab11 (Shirane and Nakayama
2006), NSF (Guo et al. 2001, Isaac et al. 2007) and
syntaxin (Simonsen et al. 1998, Hirling et al. 2000)
mediated-processes have implicated recycling endo-
some function in neurite outgrowth. For example,
overexpression of Syntaxin 16, a protein involved in
Golgi-endosomal trafficking, moderately stimulates
neurite outgrowth in primary mouse cortical neurons
(Mallard et al. 2002, Chua and Tang 2008).
CONCLUSIONS
Although enormous progress has been made over
the last decade in revealing the molecular basis of den-
dritic arbor development and its stability, many ques-
tions remain. For example, what are the exact differ-
ences, at the molecular level, between development,
stabilization and further remodeling of dendritic arbors?
The existence of such differences is obvious from sev-
eral studies, including our own work showing that
PI3K can induce dendritic growth only in a certain
timeframe during development, but is constantly need-
ed for preservation of the already formed tree (Jaworski
et al. 2005). Another problem that emerges from the
use of such distant organisms as flies and rodents,
which have very different spatial organization of den-
dritic arbors, is inaccurate generalizations of experi-
mental observation. Another issue is the identification
of executor proteins, the expression of which is con-
trolled during dendritic development by transcription
factors and local translation. Finally, much more work
needs to be done in mammalian in vivo models to
extend our understanding of the molecular mechanisms
of dendritic arbor dysfunctions that may contribute to
human nervous system disorders. Hopefully with
growing interest in molecular biology of neuronal
development these issues can be solved in a reasonable
time scale.
ACKNOWLEDGMENTS
M.U. is a holder of a scholarship of Polish Ministry
of Science and Higher Education. Work of M.B. has
been financed from NovelTune 6FP EU grant (LSH-
CT-2006-037378). This work has been financed by
Polish Ministry of Science and Higher Education (N
N301 3147 33) to J.J. We thank Marta Miaczynska,
Elizabeth Nolan and Malgorzata Skup for very helpful
comments on this manuscript.
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