Setting up presynaptic structures at specific positions.

Abstract

Precise formation of presynaptic structures at specific loci is critical for correctly wiring neuronal circuits. Recent findings have gradually revealed how essential cues from different sources inform the axon to define the presynaptic domain and to choose its postsynaptic target. Here, we review key molecular regulators which mediate instructive or repellent signals from multiple sources including the target cells, local guidepost cells, and distal guiding tissues.

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Setting up presynaptic structures at specific positions
Chan-Yen Ou and Kang Shen
Precise formation of presynaptic structures at specific loci
is critical for correctly wiring neuronal circuits. Recent
findings have gradually revealed how essential cues from
different sources inform the axon to define the presynaptic
domain and to choose its postsynaptic target. Here, we
review key molecular regulators which mediate instructive
or repellent signals from multiple sources including the
target cells, local guidepost cells, and distal guiding
tissues.
Address
Department of Biology, Howard Hughes Medical Institute, Stanford
University, 385 Serra Mall, CA 94305, USA
Corresponding author: Shen, Kang (kangshen@stanford.edu)
Current Opinion in Neurobiology 2010, 20:1–5
This review comes from a themed issue on
Signalling mechanisms
Edited by Linda van Aelst and Pico Caroni
0959-4388/$ – see front matter
# 2010 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.conb.2010.04.011
Introduction
Neurons form highly complex neural circuits through
precise synaptic connections. The accuracy of wiring
relies on the ability of each single neuron to find its
destined synaptic partners. Cell migration and axon
guidance determine the position of neurons and target
the axons to distinct regions of the nervous system [1,2].
Subsequently, the process of synaptic target selection
and synapse formation takes place, during which the
pre- and postsynaptic cells become juxtaposed against
each other. The recruitment of active zone proteins and
clusters of synaptic vesicles to the presynaptic sites
transform the adjacent axonal membrane into a highly
specialized presynaptic membrane. Growing evidence
suggests that synapses not only form between specific
pairs of cells but also at particular subcellular localiz-
ations. In this article, we will review the emerging
findings that indicate various cues from the synaptic
partner cell, local neighboring cells, the extracellular
matrix, and distal guiding tissues define the location
of presynaptic boutons. We will focus on recent dis-
coveries of key molecular regulators for this process in
vivo.
Target-derived signals induce presynaptic
formation
The striking observation that neurons in dissociated
cultures can form functional synapses argues strongly
that postsynaptic cells are sufficient to induce the de-
velopment of presynaptic terminals, and hence may
contain information to specify the location of presy-
napses in vivo. The most intuitive and probably most
accepted model for synaptic specificity is that specific
recognition molecules between the synaptic partner
cells bind and mutually induce the formation of pre-
and postsynaptic specializations. Indeed, a number of
postsynaptic adhesion molecules directly interact with
presynaptic binding partner molecules to trigger pre-
synaptic development. These cell adhesion molecules
include Neurexin/Neuroligin, SynCAM, leucine-rich
repeat (LRR) domain proteins, Cadherins, Integrins
andImmunoglobulin superfamily
[3–5].
(IgSF)proteins
Neurexin/Neuroligin and SynCAM
Neurexin/Neuroligin and SynCAM are among the ear-
liest identified synaptic cell adhesion molecules (CAMs).
It was demonstrated that the postsynaptically localized
membrane protein neuroligin, when expressed in fibro-
blasts, was sufficient to induce morphological and func-
tional presynaptic differentiation in vitro [6]. The
homophilic adhesion molecule synCAM, which has been
found at synapses, appears to have similar presynaptic
inducing activity [7]. However, the exact roles for these
proteins in synaptic specificity in vivo remain somewhat
unclear [8,9].
LRRTM
Using a similar fibroblast expression assay in an unbiased
screen, Craig and colleagues found that a family of
transmembrane proteins containing leucine-rich repeat
domains (LRRTM1-4) also possesses activity in indu-
cingpresynapticdifferentiation,
multiple classes of membrane molecules can induce
the formation of presynaptic terminals [10??]. Further-
more, two recent studies identified neurexin 1 as the
interaction partner of LRRTM2, a member of the
LRRTM family [11,12]. They showed that the postsyn-
aptic localized LRRTM2 bind to neurexin and induce
presynapse formation through this interaction. Interest-
ingly, in vivo analysis of specific synapse formation in the
Drosophila neuromuscular junction system also led to
the notion that at least four LRR proteins, caps, trn, haf,
and CG8651 contribute to the specificity of synaptogen-
esis [13??].
suggestingthat
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EphrinB
TheEphrinBsubfamilyoftheEphrinproteinscanalsobe
found at presynaptic terminals and promotes synapse
formation and maturation in the Xenopus retinotectal
system [14]. Using in vitro observations of HEK293T-
cortical neuron co-cultures, Kayser and colleagues
showed that expression of various isoforms of EphB2
was sufficient to trigger clustering of presynaptic mol-
ecules, potentially by activating EphrinB on the presyn-
aptic terminals [15].
Neurofascin
Increasing
suggest that synaptic connections are precisely estab-
lishedatspecificsubcellular
example, Purkinje neurons are innervated by two types
ofGABAergicinterneurons:stellatecellsandbasketcells
[16]. While the stellate cells innervate spines and den-
drites of Purkinje cells, basket cells specifically form
synapses on the axon initial segment (AIS). At the
AIS, a member of the L1 cell adhesion molecules, neu-
rofascin,isconcentratedandrecruitedbyankyrin-G[17].
Ango et al. found neurofascin186 (NF186) guides basket
axon terminals towards the AIS. Furthermore, they
showedthatNF186inducesthebranchingandformation
of presynaptic specializations of the basket axon, gen-
erating the characteristic brush-like ‘‘pinceau’’ synapses
[18].
anatomical andphysiological evidence
compartments. For
Sidekicks and Dscams
The precision of synaptic connectivity is evident in the
inner plexiform layer (IPL) of the retina where differ-
ent classes of bipolar, amacrine and retinal ganglion
neurons (RGCs) innervate each other within this com-
plex neuropil. Distinct populations of axons terminate
at specific depths of the IPL, forming more than ten
sublaminae [19,20??]. The IgSF proteins Sidekick-1,
Sidekick-2 and DSCAMs are each expressed by distinct
groups of RGCs and bipolar or amacrine neurons. The
homophilic adhesion properties of these molecules
form the foundation of the hypothesis that neurons
expressing a particular Sidekick or DSCAM will con-
nect to other neurons expressing the same adhesion
molecule. Consistent with this idea, depletion of side-
kicks disrupts the respective laminar-specific arboriza-
tion of RGCs, while ectopic expression of Sidekick can
redirect axons or dendrites to the respective sublaminae
[21,22]. Similarly, Dscam and Dscam-like-1 (DscamL)
are mainly involved in homophilic interactions [20??].
While the loss of Dscams disrupts the neuronal
arborization in respective sublaminae of the IPL, over-
expression leads neuronal processes to the sublaminae
with enriched Dscam [20??]. While it is not clear
yet whether the Sidekicks or Dscam can directly stimu-
late synapse formation, they are good candidates for
synapse inducing molecules that specify connection
specificity.
Off-target-derived signals inhibit presynaptic
formation
While the abovementioned target-derived molecules
potentially specify the location of presynaptic terminals
by stimulating synapse formation with a correct partner, it
is conceivable that inhibitory factors derived from incor-
rect target cells prevent ectopic synapse formation with a
wrong synaptic partner. Indeed, at least two sets of
molecules fit the bill.
Semaphorins
Semaphorin proteins, initially characterized as axon
guidance factors, can also influence local targeting
and synaptic connectivity. Overexpression of SemaII
in muscles prevents motor neuron innervation in flies
[23]. Semaphorin receptors plexin A3, plexin A4, and
neuropilin 2 are required for pruning transient axon
collaterals and removing their ectopic synaptic contacts
in the developing mouse CNS [24,25]. Recently,
Sema3e and its receptor plexin D1 (PlxnD1) were
shown to regulate two types of reflex circuitry in mice
[26??]. In wild-type animals, both cutaneous maximum
(Cm) sensory neurons and tripceps (Tri) sensory
neurons express PlexD1. Cm motor neurons specifically
express Sema3e which prevents synaptic contacts with
Cm sensory neurons. In contrast, triceps (Tri) motor
neurons do not express Sema3e and do form synapses
with Tri sensory. Removal of Sema3e or PlexD1 results
in an ectopic synaptic connection between Cm sensory
neurons and Cm motor neurons. Ectopic expression of
Sema3e in Tri motor neuron blocks its synapse for-
mation with Tri sensory neurons. Therefore, through a
repellent mechanism, Sema3e signaling determines
whether Cm and Tri monosynaptic reflex circuitry
can form.
Wnt4
Genetic analysis of the Drosophila NMJ system led to the
discovery of another target-derived repulsive cue, Wnt4.
Two similar larval ventral muscles, M12 and M13, are
parallel and adjacentwith
morphology. Still, they are innervated by different motor
neurons. Inaki et al. found that Wnt4 is preferentially
expressed in M13 [27]. Wnt4 mutants displayed reduced
motor neuron innervation on M12 and increased inner-
vation on M13. Specific labeling revealed M12-specific
motor neurons RP5 and V mistarget M13 in the Wnt4
mutant. Conversely, ectopic expression of Wnt4 in M12
alsocausedreducedM12innervationandaugmentedM13
innervation.
comparablesize and
Taken together, this emerging literature suggests that
semaphorins and Wnts secreted from local off-target
cells can dramatically influence the locations of presyn-
aptic terminals by inhibiting inappropriate synaptogen-
esis.
2
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Guidepost-derived signals specify synaptic
position
Development of synaptic circuits takes place concur-
rently with the development of non-neuronal cells and
tissues such as glia and vasculature. It is becoming
increasingly clear that neighboring non-neuronal cells
can also play important roles in positioning presynaptic
terminals at least in C. elegans.
SYG-1 and SYG-2
The C. elegans egg-laying motor neuron HSNL forms
synapses onto the VC neurons and vulva muscles near
the vulva. Surprisingly, genetically ablation of these
target cells does not affect the location of presynaptic
specification in HSNL. However, the removal of neigh-
boring vulva epithelium cells does cause defects in
synaptic specificity. Genetic analysis of this system
led to the discovery of two IgSF proteins, SYG-1 and
SYG-2. SYG-1 functions autonomously in HSNL and
accumulates at the synaptic region during synaptogen-
esis. SYG-2 is expressed by vulva epithelium cells, and
bind to SYG-1. Furthermore, ectopic expression of SYG-
2 in secondary epithelial cells relocates SYG-1 and
synaptic vesicles in HSNL, suggesting SYG-2 induces
presynaptic development and instructs the location of
synapses [28,29].
UNC-6/Netrin and UNC-40/DCC
Like the HSNL neuron, the interneuron AIY also utilizes
an external cue provided by guidepost cells to form
synapses with another interneuron RIA [30]. In a genetic
screen, a mutant of netrin receptor unc-40/DCC was iso-
lated based on the loss of AIY presynaptic structures
apposed to RIA. Since the phenotype can be cell
autonomouslyrescuedbyexpressingunc-40inAIY,netrin
signaling is unexpectedly required for presynaptic assem-
bly. Interestingly, thenetrinsignalisderived fromventral
cephalic sheath cells (VCSCs), which are astrocyte-like
cells beneath the contact region between AIY and RIA
[31,32]. Abnormal extension of VCSCs in unc-34/enable
caused ectopic AIY presynapses and an elongated RIA
process, suggesting the glia instructively match the con-
nection between AIY and RIA.
Morphogenetic gradients specify subcellular
localization of synapses
Besides local cell adhesion mechanisms, it has been
known that many secretory morphogenic factors can also
serve as prosynaptogenic cues, including Wnt family
members, fibroblast growth factors (FGFs), and bone
morphogenetic protein (BMP) [33–35]. Recently, several
findings have further unraveled how secretory factors
pattern the presynaptic specification, identifying unex-
pected roles as anti-synaptogenic cues. Two studies uti-
lizing the C. elegans tail motor neuron DA9 illustrate how
environmental cues restrict presynaptic specification to a
well-defined domain within the axon projection.
LIN-44/Wnt
The DA9 axon forms stereotyped en passant synapses in a
discrete axonal segment, connecting with VD/DD
neurons and dorsal body wall muscles. No presynaptic
structures are present in the dorsal-posterior asynaptic
domainorinthecommisureregion.ItturnsoutthataWnt
gradient formed by secretion of LIN-44 by hypodermal
cells in the tail prevents synapse formation in the ‘‘asy-
naptic’’ domain [36]. Ectopic synapse forms in this region
in the lin-44 mutant. Similar effects are found in the
deficiency of lin-17/frizzled, which encodes a WNT re-
ceptor that functions in the DA9 axon. These results
suggest that Wnts, signaling through LIN-17/Frizzled,
locally suppress synapse formation in the proximal seg-
ment of the axon.
Netrin and UNC-5
Incontrast totheWNT signal, whichgeneratesa gradient
from the posterior to the anterior, the axon-guidance
molecule, UNC-6/Netrin, is expressed in the ventral side
and forms another gradient in the dorsal-ventral axis [32].
Poon et al. discovered abnormal ventral accumulation of
presynaptic components at dendritic loci of DA9 in unc-6
mutant animals [37??]. Interestingly, the UNC-6/Netrin
signal is transmitted by the UNC-5 receptor, but not the
UNC-40 receptor as in AIY since unc-5 mutants, but not
unc-40 mutants,show phenotypes that aresimilar to unc-6.
A genetic manipulation that only removes UNC-5 at a
developmental stage after the axon is well guided can still
cause mislocalized dendritic synaptic vesicles, suggesting
the defect is not due to an axon guidance problem and
Netrin signaling is constantly required for preventing
ectopic synapses.
Taken together these findings in an invertebrate system
suggest that even global extracellular cues can affect the
positioning of presynaptic terminals.
Axon-axon interactions might specify the
location of synapses
Apartfromtheiraxonguidanceactivities,ephrinsandtheir
receptorEphsalsoregulatedendriticspinemorphogenesis
and synaptic maintenance (reviewed by Klein, 2009) [38].
In a very interesting study, Galimberti et al. studied how
the dentate gyrus (DG) granule axons within the mossy
fibers arrange their presynaptic terminals in a topographic
manner. The mossy fiber axons form large boutons (Large
Mossy Fiber Terminals, LMTs) onto CA3 pyramidal
neurons in the hippocampus. They found that about half
of these mossy fibers develop more than one intricate
Terminal Arborizations (TAs), which contains a core
LMT and multiple satellite LMTs connected to the core
LMT through processes. Notably, mossy fibers form TAs
in CA3 following a topographic rule based on their cell
body location in the DG [39??]. They further dissected
differentportionsoftheDGandCA3tissuesandidentified
a unique gradient of EphA4 in the DG. Treatment with
Presynaptic structures at specific positions Ou and Shen3
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EphA4 inhibitor abolishes the topographic distribution of
TAs in slice cultures. Further studies will be required to
understand the exact role of EphA4 in vivo and whether it
autonomouslyregulatespresynapticstructuresorreversely
signals postsynaptic components. Still, these data argue
strongly that there are mechanisms to arrange presynaptic
terminals within a neuropil. Axon–axon interaction might
be one of the sources to provide such positional infor-
mation. For example, in the fly visual system, the quan-
titative difference of the atypical cadherin Flamingo
between photoreceptor growth cones is essential for target
selection [40]. Similar arrangement of presynaptic term-
inals for en passant synapses is a robust phenomenon in
invertebrate systems such as C. elegans [41]. It is highly
likely that axon–axon interactions might also play import-
antrolesforthecorrecttopographicplacementofsynapses.
Conclusion remarks
It appears that diverse mechanisms are utilized to specify
the location of presynaptic terminals in vivo. Both induc-
tive and inhibitory cues from target and non-target tissues
play important roles to determine where and with whom
synapses form.
The cellular and molecular studies on the mechanisms of
presynapse formationhave
resembles to axon guidance mechanisms. Direct cell–cell
interaction, local cell matrix, guidepost cells, and long
rangemorphogenicgradientsdefinepresynapticdomains.
It is obvious that the consistency of target specificity is
achieved combinatorially through multiple signaling
pathways at different levels (Figure 1). Most signaling
pathways discussed here also direct axonal growth in
other systems. For example, the Netrin pathway plays
alsorevealedstriking
important conserved roles in both axon guidance and
synapse formation. Interestingly, through two sets of
receptors, Netrin can be an attractive or repulsive signal
to the growth cone while also promoting or inhibiting
presynaptic specifications. How are these ligand and re-
ceptor systems coupled to diverse intracellular signaling
pathways to mediate axon guidance and presynaptic
assembly still remains to be determined.
Setting up presynaptic structures at specific positions
requires diverse external cues and internal machineries.
Much needs to be learned regarding the mechanisms that
translate extracellular cues to internal regulation and
coordination of assembly and disassembly presynaptic
structures. Given the complexity of neuronal circuitry,
genetic tools that can label single neuron or subsets of
neurons will be required to reveal detailed synaptic
patterning and will enable studies to dissect the intricate
cell–cell interactions and intracellular signaling pathways
that achieve such precise connectivity during develop-
ment and adult plasticity.
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Figure 1
The Selection of the Presynaptic Position.
Inhibitory signals secreted from distal tissues prevent erroneous assembly of presynaptic structures. Instructive cues from apposed guidepost cells
and correct targets induce the presynaptic bouton while repulsive signals from potential off-target cells preclude inaccurate connection.
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