Download Guidance cues involved in the development of the peripheral

Autonomic Neuroscience: Basic and Clinical 112 (2004) 1 – 14
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Review
Guidance cues involved in the development of the
peripheral autonomic nervous system
H.M. Young *, R.B. Anderson, C.R. Anderson
Department of Anatomy and Cell Biology, University of Melbourne, 3010 VIC, Australia
Received 9 December 2003; received in revised form 25 February 2004; accepted 26 February 2004
Abstract
All peripheral autonomic neurons arise from neural crest cells that migrate away from the neural tube and navigate to the location where
ganglia will form. After differentiating into neurons, their axons then navigate to a variety of targets. During the development of the enteric
nervous system, GDNF appears to play a role in inducing vagal neural crest cells to enter the gut, in retaining neural crest cells within the gut
and in promoting the migration of neural crest cells along the gut. Sema3A regulates the entry of extrinsic axons into the distal hindgut,
netrin-DCC signaling is responsible for the centripetal migration of cells to form the submucosal ganglia within the gut, Slit – Robo signaling
prevents trunk level neural crest cells from entering the gut, and neurturin plays a role in the innervation of the circular muscle layer. During
the development of the sympathetic nervous system, the migration of trunk neural crest cells through the somites is influenced by ephrin-Bs,
Sema3A and F-spondin. The migration of neural crest cells ventrally beyond the somites requires neuregulin signaling and the clumping of
cells into columns adjacent to the dorsal aorta is regulated by Sema3A. The rostral migration of cells to form the superior cervical ganglion
(SCG) and the extension of axons along blood vessels involves artemin signaling through Ret and GFRa3, and the entry of sympathetic
axons into target tissues involves neurotrophins and GDNF. Relatively little is known about the development of parasympathetic ganglia, but
GDNF appears to play a role in the migration of some cranial ganglion precursors to their correct location, and both GDNF and neurturin are
involved in the growth of parasympathetic axons into particular targets.
D 2004 Elsevier B.V. All rights reserved.
Keywords: Guidance cues; Peripheral; Autonomic nervous system
1. Introduction
All peripheral autonomic neurons (sympathetic, parasympathetic and enteric) arise from neural crest cells that
migrate away from the neural tube and navigate to the
location where ganglia will form. After differentiating into
neurons, their axons then navigate to a variety of targets.
These processes rely upon molecules that are attractive or
repulsive to the migrating cells or growth cones of growing
axons. In this review, we first briefly summarize the classes
of guidance cues that are involved in neural crest cell
migration and axonal navigation during the development
of the autonomic nervous system. We then describe in detail
how different guidance molecules act at different developmental stages during the development of the enteric, sympathetic and parasympathetic nervous systems. A summary
* Corresponding author. Tel.: +613-8344-0007; fax: +613-9347-5219.
E-mail address: h.young@unimelb.edu.au (H.M. Young).
1566-0702/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.autneu.2004.02.008
of the guidance cues involved in the development of
autonomic neurons and their roles is shown in Table 1.
2. Neural guidance cues
2.1. ‘‘Classical’’ neural guidance molecules
Enormous progress has been made in the past few years
in identifying molecules that function as attractive or
repulsive cues to guide migrating neural cells and growing
axons during development. Axon guidance and directed
neural migration (collectively called ‘‘neuronal navigation’’
by Song and Poo, 2001) use common guidance molecules—
netrins, semaphorins, slits and ephrins—and it appears that
members of all of these major families of neural guidance
molecules play some role in autonomic neuron development. Neural guidance molecules and their receptors are
expressed in precise spatial and temporal patterns during
development.
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H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
Table 1
Summary of signalling pathways that influence migration and axon guidance during the development of different regions of the peripheral autonomic nervous
system
Enteric
Guidance cue
Proposed role in neural guidance
References
GDNF/GFRa1/Ret
Promote migration of vagal neural crest cells into and along
the gut, retain neural crest cells within the gut
Influence entry of extrinsic axons into the hindgut
Induce secondary migration from myenteric to submucosal
region of the gut
Induce growth of axons into circular muscle layer
Prevents trunk level neural crest cells from entering the gut
Prevent trunk neural crest cells from entering caudal half of
each somite
Young et al. (2001); Natarajan et al. (2002);
Iwashita et al. (2003)
Shepherd and Raper (1999)
Jiang et al. (2003)
Sema3A/neuropilin-1
Netrins/DCC
Sympathetic
Neurturin/GFRa2/Ret
Slit/Robo
EphrinBs/EphB3,
Sema3A/neuropilin-1,
F-spondin
Neuregulin/ErbB2, ErbB3
Sema3A/neuropilin-1
Artemin/GFRa3/Ret
NGF/TrkA
Parasympathetic
Otic ganglion
Ciliary ganglion
GDNF/GFRa1/Ret
GDNF/GFRa1/Ret
Heuckeroth et al. (1999); Rossi et al. (1999)
De Bellard et al. (2003)
Krull (2001); Halloran and Berndt (2003)
Promote migration ventral to the neural tube
Arrest migration of trunk level neural crest cells near
dorsal aorta
Induce (i) migration of cells to form superior cervical
ganglion, (ii) segmentation of cell columns into ganglia
and (iii) axon outgrowth along blood vessels
Essential for axon ingrowth into salivary glands, eye
and spleen.
Britsch et al. (1998)
Kawasaki et al. (2002)
Promote migration of neural crest cells to the correct site
Promotes projection of axons from ciliary ganglion
towards eye
Enomoto et al. (2000)
Hashino et al. (2001)
2.1.1. Netrins
Netrins are a conserved family of secreted proteins
(f 600 amino acids) that share some homology to laminin
(see Dickson and Keleman, 2002). They have been shown
to act as bifunctional neural guidance cues, exerting either
attractive or repulsive effects. To date, four vertebrate
members of the netrin family have been identified (netrins
1 –4). Netrins interact with two main families of receptors,
UNC5 and DCC (deleted in colorectal cancer) families. The
repulsive effects of netrin involve the UNC5 family of
receptors, and the attractive effects of netrin are mediated
through the DCC family of receptors, although the DCC
family of receptors have also been implicated in repulsion.
2.1.2. Semaphorins
Semaphorins are a conserved family of secreted and
membrane-bound proteins (see Pasterkamp and Kolodkin,
2003) that are predominantly known for their role in neural
repulsion. To date, more than 30 semaphorins have been
identified. Semaphorins have been classified into eight
groups on the basis of sequence similarity and distinctive
structural features. They are typically around 750 amino
acids in length and are defined by a conserved semaphorin
domain ( f 500 amino acids) that contains 14 – 16 conserved cysteines, several blocks of conserved residues and
no obvious repeat at their amino terminus. Two receptor
families have been implicated in mediating semaphorin
function, the plexins and neuropilins. Members of the
GPI-linked and transmembrane classes of semaphorins bind
directly to the plexin family of receptors. To date, at least
nine plexins have been identified and classified into four
subfamilies (plexins A –D) based on structural similarities.
Enomoto et al. (2001); Honma et al. (2002)
Glebova and Ginty (2004)
Secreted semaphorins interact directly with the neuropilin
family of receptors, which in turn form a receptor complex
with the plexins.
2.1.3. Slits
Slits are a family of large, secreted proteins containing
four leucine-rich repeats surrounded by conserved N- and
C-terminal domains, nine EGF-like repeats, an ALPS domain and a cysteine-rich carboxyl terminal domain (see
Wong et al., 2002). Slits are primarily known for their role
in neural repulsion. To date, three vertebrate members of the
slit family have been identified. Slit-induced repulsion is
mediated via a family of receptors called roundabout
(Robo). Three vertebrate members of the robo family have
been identified (robos 1– 3).
2.1.4. Ephrins
Ephrins are a family of membrane-bound proteins (see
Himanen and Nikolov, 2003) that are best known for their
role in repulsion, although attractive effects have also been
described. Ephrins are characterised by the presence of a
unique N-terminal receptor-binding domain that is separated
from the membrane via a linker of around 40 amino acids. To
date, eight ephrins have been identified and are subdivided
into two classes based on their structure and receptor binding
preferences. EphrinAs (ephrinAs 1 –5) are anchored to the
membrane via a GPI linkage and ephrinBs (ephrinBs 1– 3)
have a transmembrane region and a short, but highly
conserved cytoplasmic domain, which includes a PDZbinding motif. Ephrins interact with a family of receptors
called Ephs. Eph receptors are transmembrane proteins that
contain a highly conserved N-terminal domain followed by a
H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
cysteine-rich region and two fibronectin type III repeats in
the extracellular domain, and a conserved kinase domain, a
SAM domain and a PDZ-binding motif in the cytoplasmic
region. To date, 14 members of the Eph family have been
identified and classified into two subfamilies based on their
sequence similarity and binding affinities for the ephrins. In
general, the EphAs (EphAs 1 – 8) promiscuously interact
with the GPI-linked ephrinAs, and the EphBs (EphBs 1 – 6)
interact with the transmembrane ephrinBs. In addition to
their promiscuity, the Ephs and ephrins are unique in the fact
that they mediate bi-directional signalling, meaning that both
the Eph and ephrin can serve as a receptor and as a ligand.
2.2. Neurotrophic factors
Some molecules that are classified as neurotrophic factors because of their effects on neuronal survival can also
regulate neural migration and the direction of axon outgrowth (Markus et al., 2002). For example, it was shown
many years ago that the neurites of chick dorsal root ganglia
grow towards a source of nerve growth factor (NGF)
(Gundersen and Barrett, 1979) and that growth of sympathetic axons is induced by artificial sources of NGF in vivo
(Levi-Montalcini and Angeletti, 1968).
Members of the glial cell line-derived neurotrophic factor
(GDNF) family have also been shown to influence neural
migration and neurite outgrowth. As described in later
sections of this article, GDNF, artemin and neurturin appear
to be important guidance cues during the development of the
enteric, sympathetic and parasympathetic nervous systems.
GDNF family ligands signal through a receptor complex
composed of a signaling sub-unit, Ret tyrosine kinase, that
is common to all members of the GDNF family, and a
binding sub-unit that is specific for each ligand (GFRa1 for
GDNF, GFRa2 for neurturin and GFRa3 for artemin).
2.3. Extracellular matrix and cell adhesion molecules
(CAMs)
Extracellular matrix molecules form substrata along
which neural cells migrate and axons grow. Migrating
neural crest cells and neurites of developing autonomic
neurons express a variety of extracellular matrix receptors.
Some components of the extracellular matrix enhance or are
permissive for neural migration and axon outgrowth (for
example, laminin, collagen and fibronectin), whereas other
molecules are usually inhibitory to migration and axon
outgrowth (for example, chondroitin sulphate proteoglycan
and tenascin). The role of the extracellular matrix in neural
crest cell migration has been reviewed previously (Newgreen, 1992; Henderson and Copp, 1997; Perris, 1997), and
is only summarized briefly in the current review.
CAMs can also influence neural migration and axon
outgrowth by mediating cell –cell and cell – substrate contacts. Different CAMs can show homophilic or heterophilic
binding, or both. The role of CAMs in neural crest cell
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migration has been reviewed previously (Newgreen and
Tan, 1993) and, although there is little information available
about the role of CAMs in autonomic axon growth, some
CAMs have been shown to influence sympathetic axon
growth (see Section 3.3).
3. Development of the enteric nervous system
The vast majority of enteric neurons and glial cells arise
from neural crest cells that emigrate from the post-otic
hindbrain adjacent to somites 1– 7 (Yntema and Hammond,
1954; Le Douarin and Teillet, 1973). Vagal neural crest cells
enter the foregut, and then migrate caudally within the gut
wall to colonize the entire gut. Neural crest cells that
emigrate from the sacral level of the neural axis also give
rise to a small proportion of enteric neurons and glial cells,
mostly in the large intestine (Burns and Le Douarin, 1998).
3.1. Migration of vagal level neural crest cells into and
along the gut
In addition to the enteric nervous system, vagal level
neural crest cells give rise to other derivatives, including
ganglia of the IXth and Xth cranial nerves, components of
the cardiovascular system and contribute to the caudal
branchial arches. It has been suggested that the differential
expression of receptors by specific sub-populations of
neural crest cells could determine their migration pathway
by determining their response to localized ligands within the
embryos (Wehrle-Haller and Weston, 1997). In zebrafish,
some cranial neural crest cells appear to be specified prior to
emigration from the neural tube (Schilling and Kimmel,
1994). It is unclear whether vagal neural crest cells are
specified with an ability to enter the gut prior to emigration.
Following transplantation of pre-migratory vagal neural
crest cells from quail embryos to the trunk level of chick
embryos, quail cells were reported in the gut of the chick
host embryos (Le Douarin and Teillet, 1974). This suggests
that vagal and trunk cells show different responses to the
same environmental cues or have inherently different migratory abilities. In contrast, after performing similar experiments, Erickson and Goins (2000) reported that vagal cells
transplanted to the thoracic region migrated only as far as
the dorsal aorta, suggesting that the vagal cells are not
specified prior to emigration. The mechanisms that guide
only a sub-population of vagal level neural crest cells into
the developing gut are unknown.
In embryonic mice, Gdnf mRNA is expressed by the
foregut mesenchyme prior to the entry of vagal neural crest
cells (Natarajan et al., 2002). As vagal crest cells start to
express Ret prior to their entry into the gut (Durbec et al.,
1996), and as in vitro studies have shown that GDNF is
chemoattractive to vagal crest cells prior to their entry into
the gut, it is likely that GDNF plays a role in inducing vagal
neural crest cells to enter the gut (Natarajan et al., 2002).
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GDNF is also chemoattractive to neural crest-derived cells
within the gut (Young et al., 2001; Natarajan et al., 2002;
Iwashita et al., 2003), and thus GDNF produced by the gut
mesenchyme probably plays a role in retaining neural crest
cells within the gut so that they do not migrate into
neighbouring tissues via the mesentery, or into pharyngeal
or pelvic tissues (Young et al., 2001). GDNF may also play a
direct role in the rostral-to-caudal migration of vagal neural
crest cells along the gut. Natarajan et al. (2002) reported that
there are high levels of Gdnf mRNA expression in the
stomach and then later in the caecum, which precede the
colonization of those regions by neural crest cells. In
addition, neural crest cells may still migrate towards regions
lacking other crest cells because of the presence of available
(unbound) GDNF in the mesenchyme (Young et al., 2001).
Vagal neural crest cell migration along the gut is also
likely to be influenced by the composition of the extracellular matrix. A variety of extracellular matrix molecules,
including fibronectin, laminin, J1/tenascin, and chondroitin
sulphate proteoglycan are present within the embryonic gut
wall during the time that vagal neural crest cells are
colonizing the gut (Payette et al., 1988; Rothman et al.,
1993, 1996; Newgreen and Hartley, 1995; Rauch and
Schafer, 2003). Neural crest cells within the gut also express
a range of receptors that recognize components of the
extracellular matrix including laminin binding proteins
(Chalazonitis et al., 1997; Howard and Gershon, 1998)
and integrins (Kruger et al., 2002; Iwashita et al., 2003).
In the embryonic rat gut, neural crest cells appear to migrate
in a zone between high levels of inhibitory molecules—
chondroitin sulphate proteoglycan close to the endoderm
and J1/tenascin close to the serosa (Newgreen and Hartley,
1995). Molecules that promote neural crest cell migration,
such as fibronectin and laminin, are widely distributed and
have been proposed to play only a permissive role in the
migratory route followed by neural crest cells as they
colonize the gut (Newgreen and Hartley, 1995). Interestingly, in some mutant mice in which vagal neural crest cells fail
to colonize the entire gastrointestinal tract, there are alterations in the expression of a number of extracellular matrix
molecules in the mesenchyme of the aganglionic region
(Payette et al., 1988; Tennyson et al., 1990; Rothman et al.,
1996). However, it is unknown whether these are primary
defects or secondary defects that occur due to an absence of
enteric ganglia.
3.2. Migration of sacral level neural crest cells into the
hindgut
After emigrating from the neural tube, sacral neural crest
cells migrate ventrally towards the distal hindgut. However,
in both avian and mouse embryos, there appears to be a
delay before sacral-derived cells enter the hindgut (Burns
and Le Douarin, 1998; Burns et al., 2000; Kapur, 2000). In
chick embryos, the sacral cells aggregate into the ganglia of
the nerve of Remak (a chain of parasympathetic ganglia
found in birds), and then 3– 4 days later, after the vagal
neural crest cells have colonized the hindgut, a sub-population of cells migrate into the hindgut in close association
with the axons of neurons in the nerve of Remak (Burns and
Le Douarin, 1998). In embryonic mice, it appears that some
of the sacral-derived crest cells that cluster close to the
hindgut from embryonic day (E) 10.5 enter the distal gut
after a delay of at least 4 days, while others give rise to
neurons and glial cells of the pelvic plexus (Kapur, 2000;
R.B.A., unpublished observation).
It is unknown why there is an apparent delay in the entry
of sacral neural crest cells into the hindgut. It is possible that
there is (i) an early absence of attractive molecules in the
hindgut (or their receptors on sacral crest cells) or (ii) a
transient expression of inhibitory molecules in the hindgut.
The secreted semaphorin, Sema3A, is transiently expressed
in the distal hindgut of the embryonic chick and has been
shown to be repulsive to the axons of neurons in the nearby
nerve of Remak (Shepherd and Raper, 1999). The entry of
the axons of neurons in the nerve of Remak into the hindgut
coincides with the down-regulation of Sema3A by the outer
mesenchyme (Shepherd and Raper, 1999). As sacral neural
crest cells have been reported to migrate into the distal
hindgut along the axons of neurons in the nerve of Remak
(Burns and Le Douarin, 1998), it is possible that the
expression of Sema3A also influences the migration of
sacral neural crest cells into the gut and may be responsible
for their delayed entry (Young and Newgreen, 2001; Newgreen and Young, 2002). Interestingly, when pre-migratory
vagal neural crest cells are transplanted to the sacral level of
the neural axis, they enter the hindgut without delay (Burns
et al., 2002). These data indicate that the cue that delays the
entry of sacral neural crest cells into the hindgut is not
detected by vagal cells, and thus the signaling mechanisms
controlling the entry of vagal and sacral neural crest cells
into the avian hindgut are different.
The studies described above, and studies in which neural
crest-derived cells within the gut were localized using a
variety of markers (Kapur et al., 1992; Young et al., 1998),
suggest that there is a delay in the entry of sacral neural crest
cells into the hindgut. However, there are also some studies
that have reported an early arrival of sacral cells into the
hindgut (Pomeranz and Gershon, 1990; Serbedzija et al.,
1991; Erickson and Goins, 2000). Possible reasons for the
discrepancy between the different studies have been discussed in detail previously (see Newgreen and Young,
2002), and include surgical artifacts and mis-identification
of neural crest cells. In addition, Erickson and Goins (2000)
have suggested that different groups may have examined
different rostrocaudal levels of the hindgut; they observed
an early arrival of sacral neural crest cells into the cloaca
(the distal most part of the avian gut), but in slightly more
rostral regions, they observed the same delay in entry
reported by Burns and Le Douarin (1998). To date, there
are no published reports on the expression of Sema3A in the
cloacal wall.
H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
3.3. Centripetal migration of cells from the myenteric
region to form the submucous plexus of the gut, and from
the gut into the pancreas
In most regions of the mature gastrointestinal tract,
neurons are found in two ganglionated plexuses—an outer
myenteric plexus between the circular and longitudinal
muscle layers, and an inner submucosal plexus, at the inner
margin of the circular muscle. In the small intestine, vagal
neural crest cells migrate through the outer half of the
mesenchyme and then settle just beneath the serosa, in the
myenteric region (between where the longitudinal and
circular muscle layers will form). The colonization of the
submucosal region does not occur until several days later,
probably from a secondary migration of cells from the
myenteric region. In the hindgut, the migratory pathways
taken by the vagal cells vary between species. In avian
embryos, vagal cells migrate and settle first at the inner
margin of the developing hindgut circular muscle layer,
where the submucosal plexus will form (Burns and Le
Douarin, 1998), whereas in embryonic mice, most vagal
cells settle in the myenteric region, just under the serosa,
and then a secondary migration to the submucosal region
occurs later (McKeown et al., 2001).
A recent study has shown that the centripetal migration
of cells, from the myenteric to the submucosal region, is
mediated by netrins and DCC (Jiang et al., 2003). In
embryonic chicks and mice, the gut epithelium expresses
netrins (netrins 1 and 3 in mice and netrin 2 in chick), and
neural crest-derived cells within the gut express the netrin
receptor, DCC (Seaman et al., 2001). In vitro assays showed
that netrin is chemoattractive to enteric neural crest cells,
and importantly, in mice lacking DCC, there are no submucosal ganglia (Jiang et al., 2003). Interestingly, although
netrins are expressed by the epithelial cells, neural crest cells
do not migrate into the mucosa, but form ganglia at the inner
border of the circular muscle. Hence, there must be some, as
yet unidentified, ‘‘stop’’ mechanism that prevents them from
entering the mucosa, where the concentration of netrins
would be highest.
Neurons in the pancreas arise from cells that migrate out of
the small intestine (Kirchgessner et al., 1992). Jiang et al.
(2003) also showed that netrins are expressed by the pancreas, and that netrin-DCC signaling is required for the migration of cells into the pancreas. Mice lacking GFRa2, the
ligand binding molecule for neurturin, also show a dramatic
reduction in the number of pancreatic neurons, but it is
unclear whether this is due to a failure of their precursors
to migrate into the pancreas, or a requirement for neurturin
signaling for survival and differentiation (Rossi et al., 2003).
3.4. Projection of axons by enteric neurons
There are many different types of enteric neurons that
differ in their axon projection patterns and target cells (Costa
et al., 1996; Furness, 2000). For example, there are intrinsic
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sensory neurons that project predominantly circumferentially around the gut, ascending and descending circular
muscle motor neurons, longitudinal muscle motor neurons,
secretomotor neurons, ascending interneurons and descending interneurons. Very little is known about the mechanisms
controlling the axon projections of developing enteric neurons. Neurons begin to differentiate while vagal neural crest
cells are migrating rostrocaudally along the gut, and many of
the first axons project in the same direction (caudally or
anally) and follow the same pathway through the mesenchyme as the migrating crest cells (Young et al., 1999,
2002). In a number of other locations including ventral roots
and cranial nerves, neural crest cells are also closely associated with growing nerve fibres (Rickmann et al., 1985;
Loring and Erickson, 1987; Noakes and Bennett, 1987;
Carpenter and Hollyday, 1992; Noakes et al., 1993; Gilmour
et al., 2002). In the lateral line nerve of the zebrafish,
Gilmour et al. (2002) demonstrated that the growing axons
were the source of cues that guided the neural crest cells, but
in most instances, it is unclear whether both the neural crest
cells and the axons are responding to the same (non-neural)
environmental cue, or whether the axons or the neural crest
cells are the source of a cue. In co-culture experiments in
which vagal neural crest cells were forced to enter the distal
hindgut and migrate rostrally (rather than caudally as they
do normally), most of the neurons also projected rostrally
(rather than caudally as they do normally), indicating that
the direction of neural crest cell migration and axon projection are linked, and that the polarity of the gut itself is not an
important influence on the axon projections of the first
enteric neurons (Young et al., 2002).
Many myenteric neurons have axons that project either
orally (rostrally) or anally (caudally) to innervate the circular
muscle. The orally projecting motor neurons are cholinergic
and the anally projecting motor neurons use a combination
of neurotransmitters including nitric oxide, ATP and vasoactive intestinal peptide (Costa et al., 1996; Sang and Young,
1996; Furness, 2000). It is unknown how a differentiating
enteric neuron detects the polarity of the gut, and how the
correlation between direction of axon projection and neurotransmitter type develops—whether neurons first become
cholinergic and then project an axon orally, or whether orally
projecting motor neurons become cholinergic neurons.
Mice lacking neurturin (a member of the GDNF family)
or GFRa2, which forms part of the receptor complex for
neurturin, have a reduced number of cholinergic nerve fibres
(detected by their content of substance P or by acetylcholinesterase staining) in the circular muscle, but no change in
the number of nitric oxide-containing nerve fibres (Heuckeroth et al., 1999; Rossi et al., 1999, 2003). The number of
myenteric neurons in the small intestine and colon of mice
lacking neurturin is not significantly different from wildtype mice, and thus the deficits in the innervation of the
circular muscle are not due to reduced myenteric neuron
number (Gianino et al., 2003). As neurturin mRNA is
expressed in the circular muscle layer and GFRa2 mRNA
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H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
is expressed in myenteric ganglia during both embryonic and
post-natal development (Heuckeroth et al., 1999; Rossi et
al., 1999; Dolatshad et al., 2002), neurturin could play role in
inducing a sub-population of myenteric neurons to project an
axon into the circular muscle layer and/or influence axon
growth within the muscle. Studies in which explants of
embryonic gut were grown in organ culture have shown that
neurturin promotes neurite outgrowth (Taraviras et al., 1999;
Yan et al., 2004). In vitro, GDNF also induces neurite
outgrowth from embryonic and post-natal enteric neurons
(Schafer and Mestres, 1999; Young et al., 2001; Natarajan et
al., 2002), but its role in axon growth within the gut in vivo
is unknown.
that neural crest cell and motoneuron axon navigation
through the somites is regulated by cues arising from the
somites. The molecular basis of trunk neural crest cell
migration through the rostral half of individual somites
has been reviewed in detail recently (Krull, 2001; Halloran
and Berndt, 2003), so we will only briefly review the subject
in this article. A range of molecules are differentially
expressed by the rostral and caudal halves of somites (Fig.
1A). In chick embryos, the caudal half of each somite
expresses both Sema3A (Adams et al., 1996; Giger et al.,
1996; Shepherd et al., 1996; Eickholt et al., 1999) and
ephrin-B1 (Krull et al., 1997; Wang and Anderson, 1997;
Koblar et al., 2000), and trunk neural crest cells express
neuropilin-1 (Kawakami et al., 1996; Kawasaki et al., 2002)
4. Sympathetic nervous system
The development of sympathetic neurons can be broken
down into three major steps: (1) Neural crest cells from the
trunk level of the neural axis delaminate from the dorsal
regions of the neural folds and neural tube and migrate
ventromedially through the rostral half of each somite. (2)
After passing through the somites, neural crest cells migrate
further ventrally and coalesce into ganglia adjacent to the
dorsal aorta. (3) Molecules released by the dorsal aorta
induce the cells to differentiate into neurons, which project
axons to a variety of peripheral targets.
4.1. Emigration from the neural tube and migration
ventromedially through the rostral half of each somite
Two different pathways are followed by neural crest cells
that emigrate from the trunk level of the neural axis; a
ventromedial pathway and a dorsolateral pathway. The cells
that follow a ventromedial pathway migrate through the
rostral half of each somite and give rise to dorsal root and
sympathetic ganglia. Cells following a dorsolateral pathway
migrate under the ectoderm and give rise to melanocytes.
Cells that follow a ventromedial pathway emigrate from the
neural tube before those following a dorsolateral pathway
(Serbedzija et al., 1989; Erickson et al., 1992), and it has
been shown recently that ephrin-B ligands, produced by the
dermomyotome, prevent the early emigrating cells from
migrating into the dorsolateral path (Santiago and Erickson,
2002).
Neural crest cells following the ventromedial pathway
migrate through the rostral, but not caudal, half of each
somite (Rickmann et al., 1985; Erickson et al., 1989), and
axons of spinal motoneurons also project only through the
rostral halves of the somites (Keynes and Stern, 1988). As a
consequence, dorsal root ganglia and spinal nerves are
segmental (Keynes and Stern, 1984). Microsurgical experiments in which the rostrocaudal polarity of individual
somites was reversed (Keynes and Stern, 1984), or in which
the caudal halves of individual somites were replaced with
rostral halves (Kalcheim and Teillet, 1989), demonstrated
Fig. 1. Diagrams showing the migratory pathways of trunk neural crest cells
and the location of cues that influence their migratory behaviour. (A) Neural
crest cells are channelled into the rostral half of each somite by a
combination of repulsive cues in the caudal half of each somite including
Ephrin-Bs, Sema3A and F-spondin. See Krull (2001) for review. (B) The
migration of cells to form sympathetic ganglia is influenced by cues in the
dermamyotome, and notochord (noto) and probably also by cues expressed
by the tissue dorsal to the gut which prevent trunk neural crest cells from
entering the gut. DRG—dorsal root ganglion; PNA-binding GCs—peanut
agglutinin-binding glycoconjugates.
H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
and EphB3 (Krull et al., 1997), the receptors for Sema3A
and ephrin-B1, respectively. Both Sema3A (Eickholt et al.,
1999) and ephrin-B1 (Krull et al., 1997; Koblar et al., 2000)
have been shown to be inhibitory to migrating trunk neural
crest cells. Surprisingly, treatment of avian embryos with
soluble ephrin-B1 perturbs the migration of neural crest
cells, but not the outgrowth of axons of spinal motoneurons,
indicating that different guidance cues may be used by
axons and neural crest cells to avoid the caudal half of each
somite (Koblar et al., 2000). Some extracellular matrix
molecules that are inhibitory to migrating neural crest cells
are also present in the caudal half of each somite and are
likely to contribute to the exclusion of neural crest cells
from the caudal halves of somites (see Krull, 2001). These
include F-spondin (Debby-Brafman et al., 1999) and some
chondroitin sulfate proteoglycans (see Krull, 2001).
The expression of multiple repulsive cues by the caudal
half of each somite raises the issue of the contribution of each
guidance cue to migratory behaviour and whether there is
functional redundancy. Perturbation of ephrin-B1 signalling
in chick embryos is sufficient to perturb the segmental
migration of neural crest cells through the somites, indicating
that this signaling pathway is essential (Krull et al., 1997;
Koblar et al., 2000). However, mice lacking ephrin-B2
(which may play a similar role in crest cell migration through
the caudal half of each somite in rodents to that played by
ephrin-B1 in chick embryos) have apparently normal patterns
of neural crest cell migration through the somites (Wang et
al., 1998). Similarly, mice lacking components of the
Sema3A signaling pathway do not show any defects in their
migration through the somites (Kawasaki et al., 2002). Thus,
there appears to be redundancy in the mechanisms controlling crest cell migration through the somites in mice, which
will only be confirmed by analysis of double knockouts.
4.2. Neural crest cells coalesce into ganglia adjacent to the
dorsal aorta, and some undergo a secondary migration to
form the superior cervical ganglion (SCG)
Neuregulin signaling appears to be required for the
migration of trunk neural crest cells ventral to the somites.
The neuregulin-1 gene encodes a number of different isoforms of an EGF-like factor, whose effects are mediated by
members of the ErbB family of receptor tyrosine kinases
(Falls, 2003). Trunk neural crest cells express ErbB2 and
ErbB3, and neuregulin-1 is expressed by newly formed
somites, the mesenchyme surrounding the dorsal aorta and
by the dorsal neural tube (Britsch et al., 1998). In mice
lacking neuregulin-1, ErbB2 or ErbB3, neural crest cells
delaminate from the neural tube normally and form dorsal
root ganglia, but the cells that would normally migrate
further ventrally to form the sympathetic ganglia remain in
the dorsal half of the mutant embryos (Britsch et al., 1998).
During the migration of sympathetic neuron precursors,
neuregulin signaling is probably not acting as a directional
guidance cue, but rather as a positive regulator of cells
7
motility. Thus, in the absence of neuregulin signaling, trunk
neural crest cells appear to become immobile prematurely
and accumulate dorsally, rather than migrating ventrally to
form sympathetic ganglia (Britsch et al., 1998).
Trunk neural crest cells that migrate ventrally, beyond
the level of the neural tube and somites, coalesce into
ganglia adjacent to the dorsal aorta (Fig. 1B). In mice
lacking Sema3A or its receptor, neuropilin 1, many neural
crest cells are dispersed and are present in abnormal
locations both lateral (close to the forelimb buds) and
medial (close to the midline) to the normal locations of
sympathetic ganglia (Kawasaki et al., 2002). Sema3A is
expressed in the dermamyotome and the forelimb bud in
mice and chickens (Kawasaki et al., 2002), and also by the
notochord in chickens (Anderson et al., 2003). Kawasaki et
al. (2002) have proposed that Sema3A is a repulsive cue,
and that the migration of neural crest cells is arrested when
they are adjacent to the dorsal aorta because this location is
at the bottom of a Sema3A gradient (Fig. 1B). It is
important to note, however, that although many studies
have demonstrated that a variety of members of the Sema3
sub-family are repulsive to the neurites of sympathetic
neurons (Giger et al., 1998; Kawasaki et al., 2002; Atwal
et al., 2003), only one study (Eickholt et al., 1999) has
shown that Sema3A is also inhibitory to migratory neural
crest cells. Recent studies have shown that the repulsive
effects of the notochord on dorsal root ganglia and spinal
motoneuron axons are mediated by Sema3A plus other
unidentified repulsive signals (Anderson et al., 2003;
Masuda et al., 2003), but it is unclear whether the repulsive
effect of the notochord on migrating neural crest cells
(Newgreen et al., 1986) is mediated by Sema3A only or
by a combination of repulsive cues.
The migration of neural crest cells through the rostral
halves of the somites results in the dorsal root ganglia being
segmental (Kalcheim and Teillet, 1989). Interestingly, however, when neural crest cells cease migrating and settle
adjacent to the dorsal aorta, there is no obvious evidence
of segmentation (Fig. 2). Hence, unlike dorsal root ganglia,
the segmentation of sympathetic ganglia does not appear to
be imposed by migration of neural crest cells through the
rostral halves of the somites. Instead segmental sympathetic
ganglia are likely to form by the rostral or caudal migration
of cells within the cell columns.
The SCG is thought to arise from cells that first migrate
ventrally to coalesce into a column between cervical vertebrae C1 – C7, and then many of these cells migrate rostrally
to separate from the stellate ganglion and form the SCG
between C1 and C4 (Rubin, 1985; Nishino et al., 1999). The
rostral migration of SCG precursors appears to involve a
member of the GDNF family, artemin, acting at its receptor
complex, Ret and GFRa3. In a large proportion of mice
lacking artemin, Ret or GFRa3, the SCG is found caudal to
its normal location (Durbec et al., 1996; Nishino et al., 1999;
Enomoto et al., 2001; Honma et al., 2002). In these mutant
mice, the ventral migration of SCG precursors appears to be
8
H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
Fig. 2. Inverted fluorescence micrograph showing a lateral view of a wholemount preparation of the dorsal aorta with attached sympathetic neuron precursors
on one side only from an E10.5 mouse. The sympathetic precursors were stained using an antibody to Phox2b. At the rostral end, cells are beginning to cluster
into ganglia, but more caudally, discrete ganglia cannot be discerned. Scale bar: 100 Am.
normal but their subsequent rostral migration is perturbed
(Nishino et al., 1999; Enomoto et al., 2001). Sympathetic
neuron precursors express Ret and GFRa3, and in vivo
studies have shown that an artificial source of artemin
induces migration of developing sympathetic neurons (Pachnis et al., 1993; Durbec et al., 1996; Nishino et al., 1999;
Enomoto et al., 2001; Honma et al., 2002). Artemin is
expressed both within the SCG and in the region surrounding the SCG, consistent with a role for artemin in the rostral
migration of SCG precursors (Honma et al., 2002).
Mice lacking GFRa3 and artemin also show segmentation defects in the more caudal sympathetic ganglia (Honma
et al., 2002). In the thoracic and lumbar regions of embryonic mice, sympathetic chain ganglia form at locations
where blood vessels, at each segment, branch off the dorsal
aorta. As artemin is expressed by blood vessels (see Section
3.3), and artemin is chemoattractive to developing sympathetic neurons (Honma et al., 2002), artemin may play a role
in the rostral or caudal migration of cells that lead to the
segmentation of columns of cells into ganglia throughout
the sympathetic chain.
Trunk neural crest cells never migrate ventrally beyond
the dorsal aorta into the gut (Le Douarin and Teillet, 1973,
1974). Two inhibitory or repulsive cues have been proposed
to play a role in preventing trunk neural crest cells from
entering the gut Slit – Robo signaling (De Bellard et al.,
2003) and glycoconjugates that bind peanut agglutinin (de
Freitas et al., 2003). In chick embryos, Slit1, -2 and -3 are
expressed in the splanchnic mesoderm, dorsal to the gut, and
trunk neural crest cells express Robo receptors (De Bellard
et al., 2003; Fig. 1B). As Slit2 is repulsive to trunk neural
crest cells, it has been suggested that Slit proteins play a role
in preventing trunk neural crest cells from entering the gut
(De Bellard et al., 2003). Interestingly, vagal neural crest
cells do not express Robo receptors, and thus the colonization of the gut by vagal, but not trunk, neural crest cells has
been attributed to the lack of expression of Robo receptors
by vagal neural crest cells (De Bellard et al., 2003). Peanut
agglutinin binding is transiently observed in tissue immediately dorsal to the gut at trunk, but not vagal or sacral levels
of chick embryos (de Freitas et al., 2003). As peanut
agglutinin binds to molecules that inhibit neural crest cell
migration (Oakley and Tosney, 1991), it is possible that
peanut agglutinin-binding molecules form a barrier that
prevents neural crest cells from entering the gut at trunk,
but not at vagal or sacral levels (de Freitas et al., 2003).
4.3. Developing sympathetic neurons project an axon to
target tissues
Neural crest cells that coalesce into ganglia adjacent to
the dorsal aorta are induced to differentiate into sympathetic
neurons by members of the bone morphogenetic protein
(BMP) family, which are expressed by the dorsal aorta
(Schneider et al., 1999). Shortly after the cells start to
express catecholamine synthetic proteins and neuron-specific proteins, they extend an axon. Using a mutant strain of
mice that lacks sweat glands, Guidry and Landis (1995)
showed that the target tissue is not required to direct
sympathetic axons to the vicinity of their targets. Thus,
directional information must be provided along the pathway
navigated by sympathetic axons.
The axons of sympathetic neurons project in the grey
rami, and then join the axons of sensory and motoneurons;
these mixed peripheral nerves usually follow blood vessels
to reach their targets. In mice lacking artemin, or its receptor
components, Ret and GFRa3, many of the sympathetic
axons fail to fasciculate into bundles as they exit the
ganglia, and are stunted (Enomoto et al., 2001; Honma et
al., 2002). Artemin is expressed by cells surrounding the
developing sympathetic ganglia and also by the smooth
muscle cells of blood vessels (Honma et al., 2002), and
studies both in vivo and in vitro have shown that sympathetic axons grow preferentially towards an artifical source
of artemin (Honma et al., 2002; Yan et al., 2003). Thus,
artemin not only plays a role in the rostral migration of SCG
precursors (see above), but it also appears to play a role in
inducing sympathetic neurons to extend an axon and contributes to early sympathetic axon pathfinding by inducing
them to grow along blood vessels. Interestingly, although
the axons of sympathetic neurons run together with the
axons of sensory and spinal motoneurons in peripheral
nerves, artemin does not appear to influence the axon
projections of sensory neurons (the projections of motoneurons was not examined) (Honma et al., 2002).
Although there are little data available, it is likely that
extracellular matrix and CAMs also stimulate sympathetic
axon growth or direct growth along spatially restricted
H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
pathways. For example, the neural CAM, NrCAM, is a
ligand for another CAM, axonin-1, and both have been
localized within embryonic sympathetic ganglia (Lustig et
al., 1999). A chimeric Fc-fusion protein of the extracellular
region of Nr-CAM induces strong neurite outgrowth from
sympathetic neurons from chick embryos which can be
blocked by antibodies to axonin-1 (Lustig et al., 1999).
Hence, interactions between Nr-CAM and axonin-1 could
also promote neurite outgrowth from sympathetic neurons.
Once they are in the vicinity of the target tissue, neurotrophic factors, produced by the target tissue, may induce
sympathetic axons expressing the appropriate receptors to
enter particular targets. As most tissues that are innervated
by sympathetic axons express NGF, and as sympathetic
axons grow towards a source of NGF (Levi-Montalcini and
Angeletti, 1968), NGF is likely to play a role in inducing
axons to enter particular tissues and inducing branching
within target tissues, as well as providing trophic support.
However, it has been difficult to distinguish between trophic
and guidance roles for NGF. The exact effect of NGF on
axon outgrowth and target innervation has been examined
recently by generating mice deficient for both NGF and Bax
(Glebova and Ginty, 2004). Bax is a pro-apoptotic gene and
its absence prevents the death of neurons usually seen in
NGF knockout animals. While sympathetic neuron numbers
were normal and initial axon pathfinding largely unaffected,
analysis of NGF / ; Bax / knockouts revealed that
sympathetic axon growth into specific target organs was
affected in different ways. Some target organs lacked a
sympathetic innervation altogether (salivary glands and eye)
while others were unaffected (trachea). However, the majority of organs showed a reduced sympathetic innervation.
The spleen showed a striking phenotype, in that the ingrowing sympathetic axons grew along the lienal artery, but
stalled at the boundary of the spleen, suggesting that, in this
case, the requirement for NGF was focused at this boundary.
The study confirms that, in addition to neuronal survival,
NGF plays role in the growth of sympathetic axons into
particular targets. However, the partial innervation of many
organs in the absence of NGF confirms that successful
sympathetic axon growth into peripheral targets is likely
to depend on a range of factors with overlapping roles.
The entry of sympathetic axons into some target tissues
appears to be controlled by the neurotrophin, NT-3. In
NT-3 / mice, sympathetic axons fail to enter the pineal
gland and the external ear; infusion of exogenous NT-3
into the external ear restores the sympathetic innervation in
the mutant mice (ElShamy et al., 1996). Interestingly, in
NT-3 /
mice, the sympathetic innervation of many
target tissues is normal, demonstrating that not all sympathetic neurons have a requirement for NT-3 (ElShamy et
al., 1996).
GDNF is also expressed by a number of targets that are
innervated by sympathetic neurons (Henderson et al., 1994;
Trupp et al., 1995, 1996, 1997; Hellmich et al., 1996; Nosrat
et al., 1997; Golden et al., 1999). As neurites from SCG and
9
lumbar sympathetic ganglia grow preferentially towards a
source of GDNF in vitro (Yan et al., 2003), the presence of
GDNF in some target tissues may also contribute to inducing sympathetic axons to enter particular targets.
Extracellular matrix molecules and cell surface ligands
expressed by target tissues may also be involved in the
entry of sympathetic axons into particular targets. The
myocardium of the developing heart expresses vascular cell
adhesion molecule-1 (VCAM-1), which binds to a4h1
integrin (Wingerd et al., 2002). Sympathetic axons that
innervate the developing heart express a4-integrins, and
as function blocking antibodies to VCAM-1 or a4-integrin
significantly reduce the sympathetic innervation of the
heart, interactions between VCAM-1 and a4-integrins appear to be required for the entry of sympathetic axons into
the heart (Wingerd et al., 2002).
5. Parasympathetic nervous system
5.1. Cranial parasympathetic ganglia
Analysis of knockout mice lacking molecules required
for GDNF or neurturin signaling has revealed heterogeneity amongst cranial parasympathetic ganglia in their
requirements of GDNF family members—for example,
the sphenopalatine ganglion appears to require GDNF
and not neurturin whereas the otic ganglion requires both
GDNF and neurturin (Enomoto et al., 2000; Rossi et al.,
2000). However, in only a few instances are the precise
roles of GDNF and neurturin known. Otic ganglion precursors express both components of the GDNF receptor,
Ret and GFRa1, and GDNF is expressed in a gradient
along the route that these precursors migrate (Enomoto et
al., 2000). In mice lacking GDNF, the precursors do not
follow the normal migratory pathway, and thus GDNF
appears to act as a guidance cue for the migration of neural
crest cells to the site where the otic ganglion will form
(Enomoto et al., 2000). In the eye, both GDNF and
neurturin are expressed by the ciliary muscle and striated
muscle as the axons of ciliary neurons are growing
towards these targets, and both GDNF and neurturin
promote neurite outgrowth from ciliary ganglion neurons
in vitro (Hashino et al., 2001). In chick embryos into
which a GDNF function blocking antibody had been
injected before the ciliary neurons projected an axon, very
few ciliary neurons extended towards the eye (Hashino et
al., 2001). Hence, GDNF and neurturin probably play a
role in promoting the growth of the axons of ciliary
neurons towards their targets. The sublingual and lacrimal
glands of Gfra2 /
mice lack parasympathetic nerve
fibres, but the sympathetic innervation is unaffected (Rossi
et al., 2000). Since a deficit in the parasympathetic
innervation of the sublingual gland is already evident at
birth, neurturin signaling may also be required for the
growth of axons into this target.
10
H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
5.2. Cardiac neural crest cells
Some of the neural crest cells that emigrate from the
neural tube adjacent to somites 1– 3 migrate to the developing heart. These cardiac neural crest cells not only give
rise to the cardiac ganglia, but they also contribute to the
outflow tracts and aortic arches (Creazzo et al., 1998). The
migration of neural crest cells into the heart appears to
involve the secreted semaphorin, Sema3C (Brown et al.,
2001; Feiner et al., 2001). Sema3C is expressed in the
myocardium of the outflow tract, and Sema3C / mice die
at birth due to defects in the aortic arch and cardiac outflow
tracts caused by a failure of cardiac neural crest cells to
migrate to the correct locations (Feiner et al., 2001). As
semaphorins are best known as repulsive cues, it is interesting that Sema3C may be acting as a chemoattractant to
migrating cardiac neural crest cells.
It is unclear whether members of the GDNF family are
involved as guidance cues during development of cardiac
ganglia. Late embryonic Ret / mice have a reduced
number of neurons in the cardiac ganglia, but it is not know
whether this is caused by a defect in neural crest cell
migration, reduced proliferation or a decrease in survival
(Hiltunen et al., 2000). Furthermore, adult mice lacking
GFRa2 have a reduced density of cholinergic nerve fibres
in the ventricles and ventricular conducting system (Hiltunen
et al., 2000). However, it was not reported whether there is a
change in the number of cardiac neurons in these mice, so it is
unclear whether signaling via GFRa2 (presumably through
neurturin) plays a role in neural crest cell migration, survival
or proliferation, or inducing the axons of the cardiac neurons
to enter the ventricles.
5.3. Parasympathetic ganglia in the airways
Parasympathetic neurons associated with the airways
probably arise from neural crest cells that migrate from
the foregut into the lung buds or from neural crest cells that
migrate into the lung along the vagus nerve (Tollet et al.,
2001). GDNF is expressed by the developing lung (Towers
et al., 1998), and in vitro studies have shown that GDNF is
chemoattractive to neural crest-derived cells within the lung
and influences the direction of neurite extension (Tollet et
al., 2002). However, the role of GDNF in vivo in neural
crest cell migration into the lung and axon extension is not
known.
5.4. Pelvic neurons
Neurons in pelvic ganglia include both sympathetic and
parasympathetic neurons. Little is known about the development of pelvic neurons, although they are thought to arise
from the sacral neural crest. Mice lacking GFRa2 have a
reduced number of nitric oxide synthase-containing nerve
fibres in the penis, but a normal number of sympathetic
nerve fibres (Laurikainen et al., 2000a), but it is unknown
whether this is due to a reduced number of parasympathetic
neurons in the pelvic ganglia, reduced numbers of axons
reaching their target, reduced branching or reduced survival
(Laurikainen et al., 2000a,b). GDNF is also expressed by
some targets innervated by pelvic neurons (Laurikainen et
al., 2000b), but its role is unknown.
6. Conclusions
During the assembly of the peripheral autonomic nervous
system, migrating neural crest cells and outgrowing axons
must navigate with precision to their targets.
Although some of the inhibitory and attractive cues
and substrates that enable migrating neural crest cells and
the growth cones of autonomic neurons to navigate to the
correct target have been identified, many remain to be
identified. GDNF family members appear to play a more
prominent role in neural navigation during the development of the autonomic nervous system than they do in
other parts of the nervous system. Recent analysis of mice
with null mutations in both Bax and NGF have revealed
that NGF also plays a role in guiding axons into
particular targets, as well as its well known trophic role
for sympathetic neurons. Mice lacking individual components of the major neural guidance cue signaling pathways (semaphorin, slit, ephrin and netrin families) only
rarely have shown defects in the peripheral autonomic
nervous system. This suggests either that novel guidance
cues are important or that there is considerable redundancy. The extent of this redundancy should be revealed in
the future by analysis of double-knockout mice, or by
using electroporation to interfere with multiple pathways
in avian embryos.
There are many outstanding questions to be resolved
about the identification and role of neural guidance cues
during the development of all of the major sub-divisions
of the autonomic nervous system. During the development of the enteric nervous system, it is unknown how
different classes of developing neurons (that project in
different directions) ‘‘sense’’ the polarity of the gut. It is
difficult to imagine a gradient of a single molecule
operating along the entire gut or even along a single
gut region (e.g., small intestine). Sympathetic neurons
projecting to different targets differ in their phenotype;
it is still unclear whether developing sympathetic neurons
project randomly to different targets and the phenotype is
determined solely by the target, or whether there is some
specification prior to target contact so that specific subpopulations of neurons project their axons along different
routes (because of different responses to localized
ligands). Finally, currently very little is known about the
development of parasympathetic neurons in general, apart
from some cranial ganglia. The mechanisms by which
neural crest cells navigate to particular organs and form
ganglia are largely unknown.
H.M. Young et al. / Autonomic Neuroscience: Basic and Clinical 112 (2004) 1–14
Acknowledgements
The authors’ work is supported by the Australian Research
Council (DP0345298 and DP0452272) and the National
Health and Medical Research Council of Australia (project
grant 145628 to HMY, Senior Research Fellowship 170224
to HMY and C.J. Martin Fellowship 007144 to RBA).
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