Вы находитесь на странице: 1из 3

1 Cell

??DATE??,
200? 200?
Elsevier
Inc. DOI XXXXXXXXX
494
Cell???,
153,??MONTH??
April 11, 2013
2013 Elsevier
Inc. DOI
http://dx.doi.org/10.1016/j.cell.2013.03.031

See
version
for ??????.
See online version
foronline
legend
and references.

Netrin

Trio
DOCK180

srGAP
Sos

cc3

cc2

cc1

Sema3A

Surround repulsion

FARP
LARG
RhoGEF

Plexin

GEFs/GAPs

FasII

Sema1/4-6

ROCK
Myosin-II
Actin
Microtubules

PAK
LIMK
Cofilin

EL

P
LI

A
DI

EphrinA

Kinases
PKA
FAK
GSK3
PI3K

ephexin
Vav
-chimaerin

AM

Cytoskeleton regulatory proteins

GTPases
Cdc42
Rac
Rho

Ras-GDP

Ras-GTP

Nrp

Sema3

Grasshopper CNS axon


fasciculation

Selective fasciculation

NEURITE/CELL

Surround repulsion of peripheral


nerves in vertebrates

Abl

NEURONAL GROWTH CONE

P1
P2
P3

DCC

cc0

Robo

Slit

Commissural axon guidance


at the CNS midline

Slit
Netrin

Axon attraction and repulsion

FILOPODIA

D
T

DSCAM

Pcdh

EphrinB

EphrinA

SC/Tectum

Retinotectal mapping
in vertebrates

EphA

EphrinB
Eph

EphB

Retina

Topographic mapping

Pcdh- (22)

Variable

***
Con

Pcdh- (22)

Heteroneuronal

Con

Exon 17 (2)

Proteolytic cleavage
Regulation of expression (TF, miRNA,
multiple isoforms)
Cis inhibition
Modulation of receptors output
Forward and reverse signaling
Trafficking and endocytosis

Regulatory Mechanisms

Starburst amacrine cells in mammalian retina

**

Con

Pcdh- (14)

Genomic DNA
Variable

Exon 9 (33)

Mutant
neuron

Dscam1 mutant

Drosophila mushroom body

Exon 6 (48)

Isoneuronal

Exon 4 (12)

Genomic DNA

Wild-type

Self-avoidance

R.
Jeroen XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
Pasterkamp1 and Alex L. Kolodkin2
AUTHOR
Department
Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht,
AFFILIATIONof
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
The Netherlands; 2Department of Neuroscience, HHMI, The Johns Hopkins University School of Medicine, Baltimore, MD 21212, USA

SnapShot:
Guidance
SnapShot: Axon
XXXXXXXXXXXXXXXXXXXXXXXXXX

SnapShot: Axon Guidance


R. Jeroen Pasterkamp1 and Alex L. Kolodkin2
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience,
University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
2
Department of Neuroscience, HHMI, The Johns Hopkins University School of Medicine, Baltimore, MD 21212, USA

This SnapShot surveys general axon guidance mechanisms, focusing on ligands and receptors that direct general cellular categories of neuronal process guidance. These modes
of neuronal guidance function during embryogenesis and postnatal development, and many are phylogenetically conserved at both cellular and molecular levels (Kolodkin and
Tessier-Lavigne, 2011). Axon guidance cues bind to their cognate receptors, triggering signaling events near the growth cone cell membrane and downstream signal transduction
pathways that converge on the cytoskeleton. Protein kinases, small GTPases, cytoskeleton-associated proteins, and the proteins that regulate their activity all play central roles
in these signaling cascades. Shown in the box are additional molecular mechanisms that regulate, diversify, and expand the effects of axon guidance proteins. These examples
depicted here provide a basic foundation for understanding the full range of molecules and mechanisms that direct the establishment of neuronal connectivity.
Chemoattraction and Repulsion
Guidance of axons across the central nervous system (CNS) midline involves long-range attractive and repulsive guidance cues (Dickson and Zou, 2010; Derijck et al., 2010).
Commissural neurons in the dorsal vertebrate spinal cord, shown here in cross-section, extend commissural axons ventrally that are attracted at long range by the secreted
protein netrin, which is synthesized in the floor plate. A second secreted protein also made by the floor plate, Slit, serves to repel commissural axons only after they have crossed
the midline, preventing recrossing and allowing subsequent comississural axon anterior extension. The netrin receptor DCC and the Slit receptor Robo both initiate intracellular
signaling events that can affect cytoskeletal reorganization (Bashaw and Klein, 2010), often through regulation of Rho GTPases through the action of GEFs and GAPs such as Trio,
Dock180, srGAP, and Sos. Other cytosolic signaling components, including the tyrosine kinase Abl, participate in these signaling events, as do a range of signaling molecules
and extracellular cues, including morphogens, not shown here (Bashaw and Klein, 2010).
Surround Repulsion
Axons are often directed away from inappropriate intermediate targets by the action of repulsive cues that function in trans to provide permissive pathways through which axons
can extend. The secreted repellent semaphorin 3A (Sema3A) serves such a function for peripheral axon projections (Tran et al., 2007). For example, mouse trigeminal sensory
projections to regions adjacent to the developing eye are constrained by surrounding Sema3A; similar constraint of peripheral axon extension is directed by Sema3A at the level
of the segmented somites of the developing mouse embryo. Transmembrane Semas can serve similar functions (not shown). Semas, with the exception of most subclass-3secreted semaphorins, employ holoreceptor complexes containing Plexins as ligand-binding and -signaling receptors. Class 3 Semas include Sema3A, and generally require
neuropilin (Nrp) as a ligand-binding coreceptor. Plexin activation promotes Ras/RapGAP activity intrinsic to the plexin cytoplasmic domain and regulates downstream molecules,
including GEFs (LARG, RhoGEF, and FARP) (Pasterkamp, 2012). These signaling events alter the growth cone cytoskeleton, usually resulting in repulsive guidance.
Selective Fasciculation
Individual axons encounter a myriad of intermediate axonal targets that complicates the selective bundling, or fasciculation, of any individual extending axon with its correct
trajectory. Selective fasciculation with individual axon pathways allows axons to identify and extend along appropriate bundles, often leading to the establishment of axon scaffolds that provide a template for subsequent CNS and PNS wiring. These fasciculation events can be mediated by homophilic cell adhesion molecules. The example here in the
developing insect nervous system shows that individual axons extending from identified neurons selectively fasciculate to form specific nerve bundles. The red and orange axons
express the same adhesion molecule, the Ig superfamily protein fasciclin II (FasII), resulting in the formation of a single pioneer axon pathway, the MP1 pathway, critical for CNS
wiring (Lin et al., 1994). Ig superfamily cell adhesion molecules mediate selective axonal fasciculation from worms to mammals (Kolodkin and Tessier-Lavigne, 2011).
Topographic Mapping
A common and important neuronal projection strategy involves the retention within target of nearest neighbor relations between axons of neurons with neighboring cell bodies:
so called topographic mapping. A classic example of this wiring pattern is the projection of retinal ganglion cell (RGC) axons to subcortical targets (SC/tectum) in the vertebrate
midbrain (Feldheim and OLeary, 2010). This allows preservation of the two-dimensional retinal image onto midbrain targets, as shown here for four RGC neurons located in the
nasal (N), temporal (T), dorsal (D), and ventral (V) retina, which project to the posterior (P), anterior (A), ventral, and dorsal SC/tectum, respectively. A low-N to high-T gradient
of EphA receptor tyrosine kinase (RTK) expression in RGCs is matched by a low-A to high-P gradient of ephrin A expression in the SC/tectum. Topographic mapping along the
D-V axis also involves guidance cue gradients, shown here for EphB receptors expressed by RGCs and cognate ephrin-B-attractive ligands expressed in the SC/tectum (not
shown are countergradients of Wnts and their receptors that participate in D-V topographic mapping). Eph receptors activate a range of RTK downstream signaling pathways
(not shown) in addition to GEFs (ephexin, Vav) and GAPs (-chimaerin) (Bashaw and Klein, 2010).
Self-Avoidance
Many neurons confront the daunting task of distinguishing their own axons and dendrites from those of adjacent neurons. This comes into play when individual axons in a bundle
branch to innervate multiple targets, when neuronal dendrites elaborate complex morphologies, and when sensory neurons maximize coverage of receptive fields. A convergent
evolutionary solution to this complex problem involves the expression in any one neuron of a small subset of protein isoforms derived from a single gene that is capable of generating a vast array of distinct protein isoforms, providing each neuron with a unique identity (Zipursky and Sanes, 2010). These molecules, DSCAMs in insects and protocadherins
(Pcdhs) in mammals, have the ability to mediate homophilic adhesion events. These interactions subsequently activate intracellular signaling pathways, thus far uncharacterized, that result in repulsive interactions leading to neuronal process self-avoidance but allowing overlap with nonself processes extending from other neurons. Shown here is
DSCAM-mediated promotion of axon branching in the fly mushroom body, resulting from the expression on each axon of a small subset of the thousands of possible DSCAM
protein isoforms generated by stochastic DSCAM RNA-splicing events. Also shown is Pcdh-mediated self-avoidance by dendrites of individual starburst amacrine cells (SACs)
in the mammalian retina, here resulting from expression of a subset of Pcdh isoforms generated by use of alternative promoters (Lefebvre et al., 2012). For DSCAMs and Pcdhs,
molecular diagrams show how multiple isoforms are generated, as are proposed models for how these molecules homophilically interact.
Abbreviations
Abl, Abelson murine leukemia virus oncogene; DCC, deleted in colorectal cancer; DSCAM, Down syndrome cell adhesion molecule; FAK, focal adhesion kinase; FARP, FERM-,
RhoGEF-, and pleckstrin-domain-containing protein; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GSK3, glycogen synthase kinase 3; Ig, immunoglobulin; LARG, leukemia-associated RhoGEF; miRNA, microRNA; PAK, p21-activated kinase; PI3K, phosphoinositide-3 kinase; PKA, protein kinase A; Robo, roundabout;
ROCK, Rho-associated kinase; SC, superior colliculus ; Sos, son of sevenless; srGAP, Slit-Robo RhoGTPase-activating protein; TF, transcription factor; Vav, Vav oncogene.
References
Bashaw, G.J., and Klein, R. (2010). Signaling from axon guidance receptors. Cold Spring Harb. Perspect. Biol. 2, a001941.
Derijck, A.A., Van Erp, S., and Pasterkamp, R.J. (2010). Semaphorin signaling: molecular switches at the midline. Trends Cell Biol. 20, 568576.
Dickson, B.J., and Zou, Y. (2010). Navigating intermediate targets: the nervous system midline. Cold Spring Harb. Perspect. Biol. 2, a002055.
Feldheim, D.A., and OLeary, D.D. (2010). Visual map development: bidirectional signaling, bifunctional guidance molecules, and competition. Cold Spring Harb. Perspect. Biol. 2,
a001768.
Kolodkin, A.L., and Tessier-Lavigne, M. (2011). Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harb. Perspect. Biol. 3. Published online December 1, 2010.
http://dx.doi.org/10.1101/cshperspect.a001727.

494.e1 Cell 153, April 11, 2013 2013 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.cell.2013.03.031

SnapShot: Axon Guidance


R. Jeroen Pasterkamp1 and Alex L. Kolodkin2
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience,
University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
2
Department of Neuroscience, HHMI, The Johns Hopkins University School of Medicine, Baltimore, MD 21212, USA

Lefebvre, J.L., Kostadinov, D., Chen, W.V., Maniatis, T., and Sanes, J.R. (2012). Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488,
517521.
Lin, D.M., Fetter, R.D., Kopczynski, C., Grenningloh, G., and Goodman, C.S. (1994). Genetic analysis of Fasciclin II in Drosophila: defasciculation, refasciculation, and altered
fasciculation. Neuron 13, 10551069.
Pasterkamp, R.J. (2012). Getting neural circuits into shape with semaphorins. Nat. Rev. Neurosci. 13, 605618.
Tran, T.S., Kolodkin, A.L., and Bharadwaj, R. (2007). Semaphorin regulation of cellular morphology. Annu. Rev. Cell Dev. Biol. 23, 263292.
Zipursky, S.L., and Sanes, J.R. (2010). Chemoaffinity revisited: dscams, protocadherins, and neural circuit assembly. Cell 143, 343353.

494.e2 Cell 153, April 11, 2013 2013 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.cell.2013.03.031