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Review Article
The Involvement of Neuron-Specific Factors in
Dendritic Spinogenesis: Molecular Regulation and
Association with Neurological Disorders
Hsiao-Tang Hu, Pu-Yun Shih, Yu-Tzu Shih, and Yi-Ping Hsueh
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan
Correspondence should be addressed to Yi-Ping Hsueh; yph@gate.sinica.edu.tw
Received June ; Accepted July
AcademicEditor:DeepakP.Srivastava
Copyright © Hsiao-Tang Hu et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Dendritic spines are the location of excitatory synapses in the mammalian nervous system and are neuron-specic subcellular
structures essential for neural circuitry and function. Dendritic spine morphology is determined by the F-actin cytoskeleton. F-
actin remodeling must coordinate with dierent stages of dendritic spinogenesis, starting from dendritic lopodia formation to the
lopodia-spines transition and dendritic spine maturation and maintenance. Hundreds of genes, including F-actin cytoskeleton
regulators, membrane proteins, adaptor proteins, and signaling molecules, are known to be involved in regulating synapse
formation. Many of these genes are not neuron-specic, but how they specically control dendritic spine formation in neurons is an
intriguing question. Here, we summarize how ubiquitously expressed genes, including syndecan-, NF (encoding neurobromin
protein), VCP, and CASK, and the neuron-specic gene CTTNBP coordinate with neurotransmission, transsynaptic signaling, and
cytoskeleton rearrangement to control dendritic lopodia formation, lopodia-spines transition, and dendritic spine maturation
and maintenance. e aforementioned genes have been associated with neurological disorders, such as autism spectrum disorders
(ASDs), mental retardation, learning diculty, and frontotemporal dementia. We also summarize the corresponding disorders in
this report.
1. Introduction
e tiny protrusions emerging from dendrites known as
dendritic spines are the primary subcellular locations of exci-
tatory synapses in the mammalian central nervous system [].
Dendritic spines are typically ∼- 𝜇m in length and .– 𝜇m
in width of the spine head, with diverse morphologies, such as
mushroomlike, stubby, and thin spines. ese structures are
mainly supported by the F-actin cytoskeleton. us, F-actin
cytoskeletal proteins and regulators are important factors
for generating dendritic spines. Many membrane proteins
and adaptor and signaling molecules are also involved in
controlling dendritic spine formation and maintenance [].
Several mechanisms have been described to form dendritic
spines []. e most popular mechanism is that dendritic
lopodia serve as precursors for dendritic spine formation.
Interestingly, lopodia are ubiquitously found on various cell
types. In contrast, dendritic spines are neuron-specic struc-
tures. us, the transition from lopodia to spines should
be controlled by neuron-specic factors.
Neuron-specic factors controlling dendritic spinogene-
sisfallintotwocategories.erstgroupisproteinsspecif-
ically expressed in neurons. e second group is neuron-
specic cellular responses or processes. ese proteins or
responses directly or indirectly regulate F-actin rearrange-
ment and dynamics to promote dendritic spine formation.
Studies of cytoskeleton-associated cortactin-binding protein
(CTTNBP) and heparan sulfate transmembrane prot-
eoglycan (HSPG) syndecan- serve as examples for these two
categories, respectively. CTTNBP is a neuron-specic cyto-
skeleton-associated protein and that is enriched at dendritic
spines of mature neurons. Although syndecan- is widely
expressed in many cell types, it is highly concentrated at
Hindawi Publishing Corporation
Neural Plasticity
Volume 2016, Article ID 5136286, 10 pages
http://dx.doi.org/10.1155/2016/5136286
Neural Plasticity
CytoTMEctodomain CN
a.a. sequence
C1 C2
V
SDC4
RMKKKDEGSY
SDC1
SDC2
SDC3
RMKKKDEGSY
RMKKKDEGSY
RMKKKDEGSY
EFYA
EFYA
EFYA
EFYA
Neurobromin
Dendritic
lopodia formation
Dendritic
spine formation
CASK
DLGERK - P S SAAYQKAPTK - -
DLG-KK-P-I--YKKAPT--N
SLEEPKQANGGAYQK-PTKQE
TLEEPKQA- SVTYQK - PDKQE
F : Schematic structure and amino acid sequences of syndecans. C, conserved domain ; C, conserved domain ; Cyto, cytoplasmic
domain; SDC, syndecan-; SDC, syndecan-; SDC, syndecan-; SDC, syndecan-; TM, transmembrane; V, variable region.
synapses in neurons. Syndecan- cooperates with other pro-
teins to trigger neurotransmission through a neuron-specic
signal to induce dendritic spine formation. Genomic analyses
of patients with autism spectrum disorders (ASDs) indicated
that both CTTNBP and syndecan- were associated with
ASDs [, ]. Additionally, neurobromin, CASK, and VCP
coordinate with syndecan- to control dendritic spinogenesis
and were also associated with neurological disorders. ese
ndings suggest that these genes are critical for neuronal
function, likely through their regulation of dendritic spine
formation. In this review, we will summarize the functions
of these proteins in dendritic spinogenesis and use these pro-
teins as examples to discuss how neuron-specic molecules
coordinate with ubiquitously expressed proteins to generate
neuron-specic signals for dendritic spine formation.
2. The HSPG Syndecan-2 Triggers
Dendritic Spine Formation
2.1. Syndecan-2 Is Enriched at Dendritic Spines and Is Required
for Dendritic Spine Formation. Syndecan- is a type I mem-
brane protein with a heparan sulfate modication at its
ectodomain (Figure ) []. In mammals, the syndecan pro-
tein family contains four members, syndecan-, syndecan-,
syndecan-, and syndecan- []. In rodent brains, syndecan-
and syndecan- are the two major syndecans expressed in
neurons with dierential distribution; syndecan- is highly
concentrated at synapses, while syndecan- is distributed
along the axonal sha []. Syndecan- is involved in cell-
cell and cell-matrix interactions through its heparan sul-
fate modication. It can also bind growth factors, such as
broblast growth factor (FGF) and epidermal cell growth
factor, and it acts as a coreceptor for these growth factors [].
Syndecan- is broadly and dynamically expressed in several
tissues and cell types [, ]. During neural development,
its expression gradually increases concurrent with synapse
formation [, ]. In mature neurons, such as cultured rat
hippocampal neurons at days aer plating in vitro (DIV)
or later, syndecan- is highly enriched at dendritic spines
[, ]. More importantly, overexpression of syndecan- in
immature rat hippocampal cultured neurons, such as - DIV,
when endogenous syndecan- is not yet expressed, dendritic
lopodia are massively induced at - DIV and dendritic
lopodia are then transformed to dendritic spines at - DIV
[, ]. ose dendritic spines are expected to be functional,
as they are adjacent to the presynaptic marker synaptophysin
based on confocal microscopy [, ]. Syndecan--induced
dendritic spinogenesis serves as a model to explore the
mechanisms underlying the initiation of dendritic spinogen-
esis (namely, dendritic lopodia formation), the transition
from lopodia to spines, and dendritic spine maturation and
maintenance.
2.2. e C1 and C2 Motifs of Syndecan-2 Work Sequen-
tially to Promote Dendritic Spinogenesis. e ectodomain
of syndecan- heparan sulfate modication is involved in
cell-cell and cell-matrix interactions []. Its transmembrane
domain is required for homodimerization or oligomerization
[], which is critical for the protein-protein interactions
of syndecan- []. e cytoplasmic domain of syndecan-
contains only amino acid residues (Figure ). Although it
is short, it is divided into three motifs, conserved domain
(C), the variable region (V), and conserved domain (C).
e C and C motifs are conserved among dierent synde-
cans, while the sequences of the V regions vary (Figure ).
e C motif is essential for syndecan--induced dendritic
lopodia formation of rat hippocampal cultured neurons,
as the syndecan-ΔC mutant completely loses the ability
to promote lopodia formation and spine formation at as
well as DIV [, ]. e C is required for the dendritic
lopodia-spines transition and dendritic spine maintenance
[, ]. Expression of the C deletion mutant syndecan-
ΔC at DIV promotes dendritic lopodia formation at
DIV. However, those lopodia are unable to transform into
dendritic spine at DIV [, , ]. ese analyses indicate
that the function of syndecan- in dendritic spinogenesis can
be separated into two sequential steps, namely, lopodia and
spine formation, which are controlled by two distinct motifs
in syndecan-.
Neural Plasticity
NF1 GRD
1 2818 aa
LRD CTD
Adenylate cyclase
Ras VCP
Jn Pn SDC 2
2260
1168–1530 1545–195 0
(a)
Neurobromin
PKA p
Ena
VAS P
cAMP
VCP
Spine formation
Actin Filopodia formation
SDC2
(b)
F : Function of neurobromin in neurons. (a) Neurobromin-interacting proteins. e Jn and Pn fragments interact with syndecan-.
e leucine-rich domain (LRD) binds VCP. e GAP-related domain (GRD) downregulates the Ras pathway. Both GRD and the C-terminal
half of neurobromin are involved in adenylate cyclase activity regulation. CTD, C-terminal region. (b) Neurobromin controls dendritic
lopodia and spine formation through the PKA-Ena/VASP and VCP pathways, respectively.
Because both C and C motifs are short and lack rec-
ognizable enzymatic domains, syndecan- binding partners
have been identied to determine its molecular mechanism
underlying dendritic spine formation. Several direct binding
partners (summarized in Table ) have been identied for
the C domains of syndecan-, including neurobromin []
and ezrin []. e C motif directly interacts with syntenin
[], CASK [], and synbindin []. Among these, the inter-
actions between syndecan- and neurobromin and CASK
have been shown to be relevant in dendritic spine formation.
Because the cytoplasmic tail of syndecan- is very short, it
isunlikelythatasinglesyndecan-moleculecansimultane-
ously interact with all of its binding partners. Because the C
and C motifs are involved in two sequential processes, it
is likely that neurobromin and CASK sequentially interact
with syndecan-. Alternatively, it is possible that because
syndecan- forms at least a dimer through its transmem-
brane domain, dierent syndecan- molecules in dimers or
oligomers separately interact with neurobromin and CASK.
is would suggest that syndecan-, neurobromin, and
CASK form a single large complex. Further investigation,
including coimmunoprecipitation experiments, is required to
address this question.
2.3. Neurobromin Interacts with the C1 Motif of Syndecan-
2 and Promotes Syndecan-2-Induced Dendritic Filopodia For-
mation. Neurobromin encoded by the neurobromato-
sistypeI(NF1) gene is characterized by its RasGAP-
(Ras GTPase activating protein-) related domain (GRD)
T : SDC interacting proteins.
Binding site
in SDC
Binding site
for SDC Function
NF C LRD Filopodia formation
Ezrin C N-ter. Links to actin
cytoskeleton
Syntenin C PDZ Cell adhesion and
migration
CASK C PDZ Dendritic spine
formation
Synbindin C PDZ-like Vesicle transport
(Figure (a)) [–]. Similar to syndecan-, neurobromin is
widely expressed in dierent cell types, though its expression
levelismuchhigherinthenervoussystem[].NFisone
of the most common human inherited disorders featured
bychangesinskinpigmentation,benigntumorgrowth,and
learning diculty [, ]. Neurobromin suppresses tumor
growth through its ability to downregulate the RAS pathway
[]. In addition to its RAS activity, neurobromin can
increase cAMP concentration by activating adenylate cyclase
[]. Although the molecular mechanisms are less clear, the
GRD and C-terminal region of neurobromin are required
for cAMP pathway activation (Figure (a)) []. Both Gs-
dependent and Gs-independent pathways are involved in
neurobromin-regulated adenylate cyclase activation [].
ecAMPpathwayhasbeenshowntobeinvolvedinlearning
Neural Plasticity
and memory in Drosophila [] and dendritic spine formation
in the mammalian nervous system [].
In a yeast two-hybrid screen using dierent fragments of
neurobromin as baits, syndecan- was identied as a neu-
robromin binding partner []. Notably, neurobromin has
two independent interacting domains for the C motif of
syndecan-. One is the Jn fragment corresponding to amino
acid residues – in the GRD of human neurobromin;
the other is the Pn fragment containing amino acid residues
– (Figure (a)) []. e Jn and Pn compete for bind-
ing to the C motif of syndecan-. In addition to biochem-
ical studies demonstrating the direct interaction between
syndecan- and neurobromin, uorescence immunostain-
ing further demonstrated the colocalization of syndecan-
and neurobromin at synapses in cultured hippocampal
neurons []. Moreover, both Nf knockdown and haploin-
suciency reduce the density of dendritic spines in both rat
hippocampal and mouse cortical cultured neurons and in
brains [, ], consistent with a function of neurobromin
in regulating dendritic spine formation.
e next question is how the syndecan--neurobromin
complex regulates dendritic spine formation. One study
examined syndecan- downstream signaling for triggering
lopodia formation. Using a panel of inhibitors to sup-
press various kinase activities, protein kinase A (PKA) was
identied to be required for syndecan--induced lopodia
formation []. Combined with the analysis using dierent
motif deletion mutants of syndecan-, we found that the C
motif of syndecan- is essential for PKA-dependent lopodia
formation []. Because neurobromin interacts with the
C motif and also activates the cAMP pathway, cultured
hippocampal neurons were then used to investigate whether
neurobromin mediates syndecan--induced lopodia for-
mation. Both Nf knockdown and Jn fragment expression,
which acts as a dominant-negative to disrupt the interac-
tion between endogenous neurobromin and syndecan-,
suppress syndecan--induced dendritic lopodia formation
of rat hippocampal cultured neurons at DIV []. us,
neurobromin mediates the signal from syndecan- to the
cAMP pathway to initiate dendritic spinogenesis.
Because lopodia are supported by F-actin bundles, the
syndecan--neurobromin-cAMP pathway has to induce
F-actin polymerization and bundle formation to promote
dendritic lopodia formation. e Ena (Enabled)/VASP
(Vasodilator-Stimulated Phosphoprotein) protein family is
a group of F-actin regulators that initiate actin polymer-
ization and bundling []. PKA phosphorylation promotes
Ena/VASP protein activity to regulate the F-actin cytoskele-
ton []. Upon syndecan- overexpression, Ena/VASP phos-
phorylation increases, consistent with cAMP pathway acti-
vation. Moreover, disruption of Ena/VASP activity impairs
syndecan--induced dendritic lopodia formation []. In
summary, these studies indicate that syndecan- overexpres-
sion enhances the ability of neurobromin to activate the
PKA pathway, which then induces the Ena/VASP activity to
promote F-actin bundling and lopodia formation.
Although the PKA pathway is required for dendritic
lopodia formation, increased intracellular cAMP concen-
trations alone cannot induce dendritic lopodia formation
[], suggesting that other factor(s) are involved. From
an immunoprecipitation-mass spectrometry study, valosin-
containing protein (VCP, also known as P) was identied
as a neurobromin-binding protein []. e entire D and
D ATPase domains of VCP are required for the interac-
tion with the leucine-rich domain (LRD) of neurobromin
[]. VCP is a causative gene of inclusion body myopathy
associated with Paget’s disease of bone and frontotemporal
dementia (IBMPFD) []. IBMPFD patients frequently suer
from dementia. In addition, VCP mutations are associated
with ASDs and amyotrophic lateral sclerosis [, ]. ese
evidences suggest that VCP mutations impair brain function.
A combination of human genetic studies, mouse genetic
models, and cultured hippocampal and cortical neurons have
indicated that neurobromin interacts with VCP and guides
VCP to promote dendritic spinogenesis []. e roles of
VCP and neurobromin in dendritic spine formation may
account for the neural phenotypes in patients with mutations
in the NF and VCP genes. However, it is still unclear how
VCP regulates dendritic spine formation. To fully address the
molecular regulation of neurobromin and VCP in dendritic
spinogenesis, further studies are required.
e function of the syndecan--neurobromin interac-
tion in dendritic spine formation is summarized in
Figure (b).
2.4. CASK and Syndecan-2 Interactions Regulate Dendritic
Spine Maturation. CASK is a ubiquitously expressed gene
and is critical for brain development and function [].
MutationsinthehumanCASKgeneresultinX-linked
mental retardation and microcephaly with pontine and cere-
bellar hypoplasia [–]. CASK belongs to the membrane-
associated guanylate kinase (MAGUK) family and functions
as a scaold protein to interact with more than two dozen
cellular proteins []. It is widely distributed in neurons,
including synapses, dendrites, axons, and soma []. At
synapses, it localizes to both pre- and postsynaptic sites [].
In mouse pontine explants and rat hippocampal cultured
neurons, CASK knockdown impairs synapse formation at the
pre- and postsynapse, respectively [, ]. At presynaptic
sites, it binds the membrane protein neurexin and other
scaold proteins, such as Mint, mLin, and liprin, to control
presynaptic button formation [–]. CASK uses its PDZ
domain at the postsynaptic site to interact with the C
motif of syndecan- []. In cultured hippocampal neurons,
expression of the PDZ alone of CASK or the C-terminal
tail of syndecan- that disrupts the interaction between
endogenous CASK and syndecan- reduces dendritic spine
density, narrows spine heads, and shortens spine length at
DIV, suggesting that the CASK-syndecan- interaction is
critical for dendritic spine formation [].
To investigate whether CASK is involved in dendritic
spinogenesis initiation or dendritic spine stabilization, a
time course study using a knockdown approach in cultured
hippocampal neurons has been performed []. e time
window of – DIV covering the initiation toward matura-
tion of dendritic spinogenesis was used for analysis. At DIV,
Neural Plasticity
Filopodia-spines
transitionSpine maintenance
LIN7
NMDAR
SDC2
C2 C2
GSN
P4.1
SUMO
CASK
CASK
Ca2+
F : Syndecan- coordinates with calcium inux to control
dendritic spine formation and maturation. Syndecan- links the
CASK-mLIN-NMDAR complex through its C motif and directs
this complex to target to lopodial tips. It increases the accessibility
of postsynaptic lopodia to presynaptic stimulation, which is critical
for calcium inux to induce the lopodia-spines transition. In
addition to linking mLIN and NMDAR, CASK interacts with
the protein .-F-actin cytoskeleton. is interaction provides a
physical link between the membrane and cytoskeleton to stabilize
the dendritic spine structure. GSN, gelsolin.
wild-type dendritic spines are immature, long, and thin, and
they are present at a low density. As they mature at DIV,
dendritic spine density increases, spine length decreases, and
spine width increases. Compared to control neurons, CASK
knockdown does not aect spine density, length, or size at
DIV, suggesting that CASK is not critical for dendritic
spinogenesis initiation. At DIV, CASK knockdown induces
dendritic spines withdraw and the spine heads fail to enlarge.
e spine density is decreased compared to control neurons
[]. e data indicate that CASK is important for dendritic
spine maturation, likely by linking the membrane protein
syndecan- to the F-actin cytoskeleton via protein . to
stabilize dendritic spines (Figure ) [].
2.5. Neurotransmission-Induced Calcium Inux Is Critical
for the Syndecan-2-Induced Filopodia-Spines Transition. In
human embryonic kidney HEK cells, syndecan- over-
expression induced numerous lopodia on the cell surface
[]. However, these lopodia cannot mature into spines.
Because neurobromin and CASK are also expressed in
HEK cells, the aforementioned studies cannot explain
why syndecan--induced dendritic spines are only present in
neurons. A neuron-specic factor must be present to control
dendritic spine formation. Because neurotransmission is a
neuron-specic event and because dendritic lopodia are
able to receive neurotransmission signals from presynaptic
buttons [], neurotransmission seems a likely factor that
triggers the lopodia-spines transformation in a neuron-
specic manner. Indeed, EGTA treatment to chelate extra-
cellular calcium or AP treatment to block NMDAR activity,
a major neurotransmitter gated calcium channel, impairs
the endogenous lopodia-spines transition at – DIV
and syndecan--induced lopodia-spines transition at –
DIV []. In syndecan--overexpressing neurons, intracellu-
lar calcium concentration is increased compared to control
neuronsatDIV.isincreaseisduetoNMDAR-regulated
calcium inux because AP treatment eectively reduced the
intracellular calcium concentration induced by syndecan-
[]. e C motif of syndecan- is required for syndecan-
overexpression-induced calcium inux [], suggesting that
the interaction with CASK is involved in calcium inux.
Previous studies have shown that CASK interacts with mLIN
via the L domains in both proteins [–] and that mLIN
interacts with the C-terminal tail of NMDAR subunit b
(NMDARb) through its PDZ domain []. us, the CASK-
mLIN complex links NMDAR to syndecan-. e interac-
tion between syndecan-, CASK, mLIN, and NMDARb
facilitates NMDAR localization to the tips of dendritic
lopodia, where NMDAR may be activated by presynaptic
stimulation, namely, glutamate, and induce calcium inux.
Disruption of the syndecan-, CASK, mLIN, and NMDAR
complex by overexpressing the interacting domains impairs
NMDAR lopodial distribution, calcium inux, and the
lopodia-spines transition [], suggesting that syndecan-
triggers calcium inux via the CASK-mLIN-NMDAR com-
plex and induces the lopodia-spines transition (Figure ).
e morphological feature of the lopodia-spines tran-
sitionisdendriticspineheadenlargementandspinelength
shortening. e F-actin cytoskeleton must be rearranged to
allow for this morphological change. Calcium is known to
regulate F-actin dynamics in dendritic spines [–], and
gelsolin is a calcium-activated F-actin regulator. It acts as
an F-actin severing and capping protein [–]. Gelsolin
deciency impairs lopodial retraction of developing neu-
rons [] and inhibits activity-dependent F-actin remodel-
ing in mature dendritic spines []. It is also critical for
the lopodia-spines transition induced by the syndecan-
-CASK-mLIN-NMDAR complex, as gelsolin knockdown
maintains syndecan--induced protrusions at the lopodial
stage []. It is possible that other calcium regulated F-actin
regulators also act downstream of syndecan- to control the
lopodia-spines transition. More investigations are required
to further elucidate the regulation.
2.6. Conclusion of the Role of Syndecan-2 Signaling in Den-
dritic Spine Formation. rough its interactions with intra-
cellular binding partners, the ubiquitously expressing protein
syndecan- modulates the F-actin cytoskeleton, triggers neu-
rotransmission, and promotes neuron-specic synapse for-
mation. From dendritic lopodia formation, lopodia-spines
transition to dendritic spine maturation, syndecan- interacts
with dierent binding partners to control F-actin behaviors.
Syndecan- rst activates the PKA pathway via neuro-
bromin to promote F-actin polymerization and bundling for
Neural Plasticity
dendritic lopodia formation []. It recruits NMDAR to
lopodial tips through its interaction with the CASK-mLIN
complex and increases the postsynaptic responsiveness to
presynaptic stimulation []. Calcium inux induces F-actin
cytoskeleton rearrangement to allow for the morphological
change from lopodia to spines []. To further promote
dendritic spine maturation and maintenance, syndecan-
binds to the protein . through interactions with CASK [].
roughout the entire process, neuron specicity falls within
NMDAR-mediated calcium inux, which induces F-actin
cytoskeleton remodeling to result in morphological changes
to the dendritic spine. ese studies provide a comprehensive
example of how a neuron-specic ion channel coordinates
with other adhesion molecules and synaptic proteins to
control dendritic spine formation.
3. The Neuron-Specific Cytoskeleton
Regulator CTTNBP2 Is Highly Associated
with Autism Spectrum Disorders
To identify a neuron-specic F-actin regulator involved in
dendritic spinogenesis, we searched the database and litera-
ture and focused on cortactin-binding protein (CTTNBP).
CTTNBP gene encodes a brain-specic protein that inter-
acts with the SH domain of cortactin through its proline-
rich domain []. Cortactin promotes and stabilizes F-
actin branching [, ] and thus plays a critical role for
dendritic spine morphological maintenance []. Because
cortactin is a ubiquitously expressed protein, its function in
controlling dendritic spinogenesis must be regulated by a
neuron-specic factor. e specic expression of CTTNBP
in the brain makes it a good candidate to control cortactin
in dendritic spinogenesis. Furthermore, de novo mutations
in the CTTNBP gene have been repeatedly identied in
ASDpatients[,,].Inagenomicanalysiscovering
ASD patients, results indicated that CTTNBP is a high-
condence risk factor for ASDs with a false discovery rate less
than .% []. ese genetic data support a critical role for
CTTNBP in brain development and function.
3.1. CTTNBP2 Variant Transcripts and ASD Mutations. In the
expression tag sequence (EST) database (http://www.ncbi
.nlm.nih.gov/), three variants have been identied as
CTTNBP transcripts, namely,CTTNBP-Short (CT TNBP-
S), CTTNBP-Intron (CTTNBP-I), and CTTNBP-Long
(CTTNBP-L). Based on the nucleotide sequence, the rst
predicted amino acid residues are shared among all
variants []. Using an antibody against the common region
of the CTTNBP variants, immunoblotting revealed that the
Short form of CTTNBP is the predominant protein product
in brains. e protein products of the Intron and Long forms
are undetectable in adult brains []. us, the following
studies of CTTNBP in neurons focused on CTTNBP-S.
It is still unclear whether the CTTNBP-I and CTTNBP-L
variants play any role in neurons. erefore, mutation
analysis of ASD patients is meaningful when the mutation
was located within the CTTNBP-S variant sequences.
Seven de novo ASD mutations in the CTTNBP gene have
been identied in the exons encoding CTTNBP-S []. To
further explore the association of CTTNBP with ASD,
these mutations should be investigated in detail to determine
their eects on CTTNBP molecular function and neuronal
morphogenesis.
Analysis of the amino acid sequence of CTTNBP-S
predicts a coiled-coil domain at the N-terminal region and
proline-rich domain at the C-terminus. e middle region
does not contain any recognizable protein structure []. e
N-terminal coiled-coil domain mediates CTTNBP-S
homooligomerization and heterooligomerization of
CTTNBP-S and the striatin family [, ]. e C-termi-
nal proline-rich domain interacts with cortactin []. e
middle region is required for the protein’s association with the
microtubule cytoskeleton []. e functions of these inter-
actions are discussed below (Figure ).
3.2. CTTNBP2-S Controls Cortactin Mobility and Regulates
Dendritic Spine Formation and Maintenance. CTTNBP-
S localizes to dendritic spines to control the cortactin-
F-actin cytoskeleton. Both endogenous CTTNBP-S and
overexpressed Myc-tagged CTTNBP-S were found to be
highly concentrated at dendritic spines in mature cultured
hippocampal neurons. Immunouorescence analysis of adult
brains also indicated that CTTNBP-S colocalized with F-
actin puncta in vivo, presumably to dendritic spines [].
CTTNBP-S is critical for dendritic spine formation, as
CTTNBP knockdown right before dendritic spinogenesis
at DIV reduces spine density and spine head width mea-
sured at DIV. Consistent with the morphological changes,
the frequency of mEPSC (miniature excitatory postsynaptic
synaptic current) is lower in CTTNBP knockdown neurons
at DIV []. In addition to dendritic spine formation,
CTTNBP-S is involved in dendritic spine maintenance, as
CTTNBP-S knockdown in mature neurons, such as DIV,
still reduces dendritic spine density at DIV []. Cor-
tactin is required for CTTNBP-S’s regulation of dendritic
spinogenesis, as a CTTNBP-S mutant that cannot interact
with cortactin cannot rescue CTTNBP knockdown-induced
spine deciency []. Moreover, uorescence recovery aer
photobleaching (FRAP) analysis indicates that CTTNBP-S
regulates cortactin mobility in mature dendritic spines. In the
presence of CTTNBP-S, cortactin more stably localizes to
dendritic spines. e data suggest that CTTNBP-S retains
cortactin in dendritic spines and controls dendritic spine
formation and maintenance [].
CTTNBP-S also controls distribution of striatin family
proteins in dendritic spines []. e striatin protein fam-
ily contains three mammalian members, namely, striatin,
zinedin, and SGNA. ey function as B-type regulatory
subunits of protein phosphatase A (PPA) to control PPA
subcellular location and substrate specicity [, ]. All
three striatin family members are highly enriched in den-
dritic spines []. Striatin protein distribution to synapses
is mediated by its interactions with CTTNBP-S through
the N-terminal coiled-coil domains of both CTTNBP-S
and striatin family members. Similar to cortactin, CTTNBP
Neural Plasticity
NC
1 118 258 523 630
CC Mid P-rich
Striatin
Self-oligomerization Microtubule Cortactin
(a)
Axonal outgrowth Dendrite development Synapse formation
and maintenance
CTTNBP2
Stable microtubule
Unstable microtubule
Actin lament
Cortactin
Striatin/PP2A complex
CTTNBP2 KD CTTNBP2 KD
(b)
F : CTTNBP and neuronal dierentiation. (a) Schematic domain structure and CTTNBP-S-interacting proteins. CC, coiled-coil
domain; Mid, middle region; P-rich, proline-rich domain. (b) e function of CTTNBP-S in neuronal morphogenesis. CTTNBP-S controls
microtubule stability in the dendritic shas and cortactin mobility in dendritic spines. Upon CTTNBP knockdown during dendritic
extension, dendritic complexity decreases. During synaptogenesis, CTTNBP-S helps maintain cortactin in dendritic spines and promotes
dendritic spine formation and maintenance.
knockdown impairs dendritic spine targeting of striatins [].
In conclusion, CTTNBP-S regulates F-actin dynamics and
PPA signaling at dendritic spines.
3.3. CTTNBP2-S Modulates Microtubule Stability and
Regulates Dendritic Arborization. In COS cells, exogenous
CTTNBP-S was unexpectedly associated with the micro-
tubule cytoskeleton in addition to the cortactin-F-actin cyto-
skeleton []. Cell-matrix interactions inuence the cyto-
skeleton association of CTTNBP-S. In COS cells,
CTTNBP-S preferentially associates with the F-actin cyto-
skeleton within one hour aer plating. CTTNBP-S gradually
shis its preference to the microtubule cytoskeleton when
establishing cell-matrix interactions []. CTTNBP-S cyto
skeletal associations also change in neurons. CTTNBP-S is
highly concentrated at dendritic spines in mature neurons
where CTTNBP-S interacts with F-actin cytoskeletons.
In the premature stages when dendritic spines have not
yet formed, CTTNBP-S is already expressed and forms
puncta attached on microtubule bundles along the dendritic
sha []. e association of CTTNBP-S with microtubules
increases microtubule stability by bundling the microtubules.
Two CTTNBP-S domains are required for microtubule
bundling. e Mid domain is required for the association
of microtubule, and the N-terminal coiled-coil domain is
involved in CTTNBP-S oligomerization. Oligomerization
allows the CTTNBP-S oligomer to contain multiple micro-
tubule binding sites to induce microtubule bundling [].
During the dendritic extension stage, CTTNBP-S knock-
down or disruption of microtubule bundling by overexpres-
sion of the N-terminal coiled-coil domain or Mid domain
impairs dendritic arborization []. e studies suggest that,
in addition to controlling the F-actin cytoskeleton,
CTTNBP-S regulates microtubule stability to inuence
dendrite morphology.
3.4. Outstanding Questions about CTTNBP2. e dual roles
of CTTNBP-S in controlling F-actin and the microtubule
cytoskeletons require further investigation. As a neuron-
specic morphology regulator and a high-condence risk
factor for ASDs, CTTNBP deserves further study. Several
questions remain to be addressed. For instance, what is the
molecular mechanism regulating the association between
CTTNBP-S and F-actin and microtubules? Are the associa-
tions of CTTNBP-S with F-actin and microtubules mutually
exclusive? Alternatively, can CTTNBP-S act as a bridge to
link F-actin and microtubules? Only cultured hippocam-
pal neurons have been examined in functional studies of
CTTNBP-S. In the future, in vivo studies should be con-
sidered. Particularly, to address the association of CTTNBP
with ASDs, a mouse genetic model is required. e impact
of CTTNBP ASD mutations on the molecular function
Neural Plasticity
of CTTNBP-S, brain development, and cognition must be
studied to further understand the biological signicance of
CTTNBP.
4. Conclusions
Although hundreds of genes are involved in dendritic spine
formation, they should be either neuron-specic or directly
or indirectly controlled by or linked to neuron-specic
signaling or proteins to specically regulate dendritic spine
formation in neurons. In this review, syndecan--induced
dendritic spine formation and the role of CTTNBP-S in con-
trolling neuronal morphology provide two distinct examples
of how neuronal morphology can be regulated in a neuron-
specic manner. e regulation of neuronal morphology
is critical for normal brain function. Understanding these
regulations is crucial for basic research and for understanding
neurological disorder etiology, which could contribute to
potential therapeutic treatments of the diseases.
Conflict of Interests
e authors declare no competing nancial interests.
Acknowledgments
is work was supported by grants from Academia Sinica
(AS--TP-B) and the Ministry of Science and Technology
(MOST --B--, --B--, and -
-B--) to Yi-Ping Hsueh. Hsiao-Tang Hu is sup-
ported by the Postdoctoral Fellowship of Academia Sinica.
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