Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032
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ABSTRACT |
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The enteric nervous system is derived from the
vagal, rostral-truncal, and sacral levels of the neural crest. Because
the crest-derived population that colonizes the bowel contains
multipotent cells, terminal differentiation occurs in the gut and is
influenced by both the enteric microenvironment and the responsivity of
multiple lineages of precursors. Enteric growth factor-receptor
combinations, which promote the development of enteric neurons
and/or glia in most of the gastrointestinal (GI)
tract, include glial cell line-derived neurotrophic
factor-GFR-1-Ret, NT-3-TrkC, a still-to-be-identified neuropoietic
cytokine-ciliary neurotrophic factor receptor-
, serotonin
(5-HT)-5-HT2B, and LBP110, a
110-kDa laminin-1 binding protein. A qualitatively different effect is
shown by the peptide-receptor combination
ET-3-ETB, which inhibits neuronal
differentiation and appears to prevent the premature differentiation of
enteric neurons before colonization of the GI tract has been completed (resulting in aganglionosis of the terminal colon).
growth factors; glial cell line-derived neurotrophic factor; Ret; endothelin-3; endothelin B; serotonin; Hirschsprung's disease
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ARTICLE |
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EVER SINCE BAYLISS AND Starling published the results of their pioneering studies of motility in dog intestine (see Ref. 13 for references), it has been (or should have been) clear to anyone who thought about the innervation of the bowel that the enteric nervous system (ENS) cannot be like any other part of the peripheral nervous system (PNS). Bayliss and Starling's experiments, dramatically confirmed 18 years later by Trendelenburg, who demonstrated that the peristaltic reflex could actually be elicited in vitro (a situation in which the brain, spinal cord, dorsal root, and cranial ganglia have all been discarded), established that the bowel can manifest neurally mediated reflex activity in the absence of input from the central nervous system (CNS). No other component of the PNS can act similarly, that is, as an independent center of integrated neuronal activity. To carry out its unique "brainlike" functions, the ENS acquires, during its development, complex microcircuits, which include not only the excitatory and inhibitory motoneurons that innervate smooth muscle, glands, and blood vessels but intrinsic primary afferent neurons and interneurons as well. The structure of the ENS is as unusual as is its functional capability. Instead of Schwann cells, enteric neurons are supported by glia, which resemble astrocytes, and enteric neurons live in a milieu free of collagen, just like their CNS counterparts. The neurons found in enteric ganglia also exhibit an extensive array of neurotransmitters and neuromodulators, in abundance exceeding those found in the ganglia of any extraenteric portion of the PNS. In both ultrastructural and neurochemical senses, therefore, the ENS is as brainlike as it is in its ability to serve as an independent center of integrative neural activity.
The special nature of the ENS implies that the story of its development cannot be a banal recapitulation of the ontogeny of other sets of peripheral ganglia. Clearly, something has to occur during embryonic or fetal life that sets the ENS apart from the other divisions of the PNS. Given the resemblance of the ENS to the CNS, it is reasonable that lessons learned in analyzing ENS development may prove to be more applicable to understanding the ontogeny of the brain than similar studies of admittedly simpler autonomic relay ganglia. This potential for the provision of insight relevant to the brain has accounted, in part, for a recent flowering of investigations into ENS development. The use of the ENS as a model nervous system, however, does not fully account for the recent burgeoning of enthusiasm for enteric developmental neurobiology. An additional factor has been the unwitting recruitment to gastrointestinal research of investigators who have been surprised to find major defects in the ENS following the knockout of murine genes not previously known to affect the gut, such as those encoding endothelin-3 (ET-3) or its receptor, endothelin B (ETB) (1, 15). The obvious clinical significance of ENS development has also acted as a catalyst for basic research on this subject. Congenital neuromuscular disorders of the bowel are both common and serious. Understanding their pathogenesis and devising means to prevent them are thus important investigative goals.
The unique nature of the function, structure, and chemistry of the ENS is not matched by the source of its neural and glial precursors. These cells, like the majority of other peripheral neurons and Schwann cells, are the descendants of émigrés from the neural crest (19). To be sure, only three axial levels of the crest have been shown to contribute precursor cells to the ENS. These include the vagal (19), rostral-truncal (8), and sacral (19, 22, 28) levels. The vagal crest is the most significant of the three because it colonizes the entire gut. In contrast, the rostral-truncal crest colonizes only the esophagus and adjacent stomach, whereas the sacral crest is restricted in its colonizing territory to the postumbilical bowel.
One might imagine that ENS precursors could be derived from specific regions of the crest because premigratory cells in these zones are already predetermined to "find" the gut and differentiate as enteric neurons or glia. That expectation, however, has turned out not to be the case. Regions of the premigratory crest can be interchanged in avian embryos without interfering with the formation of an ENS. For example, cells from axial levels of the crest that do not (if left undisturbed) migrate to the bowel have been demonstrated to colonize the gut and form an ostensibly normal ENS when they are transplanted to the vagal region of a host embryo (19). The populations of premigratory and migrating crest cells, moreover, contain precursors that are multipotent (see Ref. 12 for references). Even more surprising, the population of crest-derived cells destined to colonize the bowel still contains pluripotent precursor cells. These observations imply that 1) the gut wall is itself a critical site where terminal differentiation of enteric neurons and glia occurs and 2) the enteric microenvironment has an opportunity to play a vital role in determining what kind of nervous system arises within the bowel.
Work on the role of the enteric microenvironment in determining the fates of crest-derived cells was greatly enhanced by the development of an effective means (immunoselection) of isolating crest-derived cells from the developing bowel (21). Immunoselection and the subsequent culture of the isolated enteric crest-derived cells in defined media make it possible to determine the direct effects of putative growth factors on the precursors of neurons and glia. Immunoselection of enteric crest-derived cells also provides relatively pure populations of such cells for the analysis of their receptors, transcription factors, or other developmentally relevant molecules. Isolation of crest-derived precursors and culture in defined media is needed because experiments carried out with mixed populations of cells, or with cells cultured in serum-containing media, cannot be interpreted. The analyses of data obtained under those conditions are confounded by the uncontrolled interactions crest-derived cells may have with their non-crest-derived neighbors and by the potential effects of unknown substances present in complex media. The immunoisolation of crest-derived cells from the fetal enteric mesenchyme has now made it possible to identify specific molecules in the wall of the gut that influence the development of enteric neurons and/or glia.
Historically, the first molecule found to affect the development of
enteric neurons and glia was a neurotrophin. Although the development
of the ENS had clearly been shown to be independent of nerve growth
factor, the more recently discovered neurotrophin-3 (NT-3) turned out
to be a potent and specific promoter of the development of both enteric
neurons and glia (4). Moreover, cells in the fetal bowel were found to
express TrkC, the high-affinity receptor for NT-3, and these cells were
found to be crest derived. Overexpression of NT-3, targeted by the
dopamine--hydroxylase promoter to developing enteric neurons (see
Refs. 17 and 18 for references), causes an increase in the size of
developing ganglia in the myenteric plexus of transgenic mice as well
as an increase in the size of the neurons they contain (unpublished data). The ENS, however, is relatively normal in the bowel of mice
following the knockout of NT-3 (10), suggesting either that
compensatory mechanisms can substitute for the loss of NT-3 during
development or, more likely, that NT-3 affects the development of only
a relatively small subset of enteric neurons or glia.
More recently, stimulation by glial cell line-derived neurotrophic
factor (GDNF) has been demonstrated to be an absolute requirement for
the survival of the vagal and sacral crest-derived cells that colonize
the gut. If either GDNF (20, 27) or its signaling receptor, Ret (26),
are knocked out in developing mice, the gut becomes totally aganglionic
below the level of the rostral foregut. ENS development, therefore,
completely fails in the vagal and sacral domains of the bowel and
persists only in the small region of the gut that is colonized by cells
from the truncal crest. GDNF, as one would expect, has been found to be
a potent promoter of neuronal development in vitro (6, 14). Early in
development [through embryonic day 12 (E12) in
rats], GDNF acts as a mitogen (6), greatly expanding
the numbers of enteric crest-derived neural precursors, but, later,
GDNF loses its ability to promote proliferation and acts only as a
growth-differentiation factor, supporting enteric neuronal but not
glial development. In addition to GDNF, which is supplied to developing
crest-derived precursors by the mesodermally derived cells of the
enteric mesenchyme, the developing gut contains GFR-1, a peripheral
glycosylphosphoinositol-anchored molecule that binds GDNF and is
necessary for the activation of Ret (30). mRNA encoding GFR
-1 is
found both in crest- and non-crest-derived cells of the enteric
mesenchyme, but GFR
-1 immunoreactivity can be demonstrated only on
crest-derived cells (6). These observations suggest that GFR
-1 may
be produced by both crest- and non-crest-derived cells in the wall of
the gut, but only cells from the neural crest anchor it to their plasma
membranes (perhaps in a complex with Ret). If so, then the gut may have
evolved a fail-safe mechanism for the provision of adequate amounts of
GFR
-1, which, as much as GDNF, is critical for the survival of the
crest-derived cells that colonize most of the bowel. GFR
-1 can be
produced by the Ret-expressing cells that require it (an interaction
called "in cis") or by
neighboring cells that by secreting the molecule also make it available
to be anchored to the membranes of the crest-derived cells that express
Ret (an interaction called "in
trans") (30).
Thus far, GDNF has been the only growth factor observed to be globally
required for the development of all enteric neurons and glia. Other
growth factors appear to be more like NT-3 in that they are needed only
for the development and/or survival of restricted subsets of
enteric neurons and/or glia (2, 12). In fact, the initial
GDNF-dependent precursor that colonizes the bowel gives rise to
multiple lineages of crest-derived successors that can be defined by
their requirements for particular growth or transcription factors. For
example, the targeted mutation of mash-1, a proneural gene that is the
mammalian homologue of the achaete-scute complex of
Drosophila, causes the esophagus to
become aganglionic and leads also to the loss of about one-third of the neurons in the remainder of the bowel. The truncal crest, therefore, which as noted above is Ret independent (8), is
mash-1 dependent. The Ret-dependent
vagal and sacral crest-derived cells, which fail to develop in
mash-1 (/
) animals,
comprise a set of neural precursors, which are all transiently
catecholaminergic and give rise to the earliest born of enteric
neurons. This set includes all of the serotonergic neurons of the gut
[which are missing in mash-1
(
/
) mice] and probably also excitatory and
inhibitory motoneurons. In contrast, the neurons that are
mash-1 independent are never
catecholaminergic and are not born until relatively late in ontogeny.
All enteric neurons that contain calcitonin gene-related peptide are
members of this set.
Additional enteric neuronal precursor lineages can be defined by growth
factors required only by still smaller subsets of the neurons that
develop from mash-1-dependent
precursors. For example, enteric motoneurons appear to be derived from
precursors in the mash-1 lineage that
require stimulation of a still-to-be-identified neuropoietic cytokine
that interacts with the -component of the ciliary neurotrophic
factor receptor (CNTFR
) (see Ref. 5 for references). The circular
muscle layer lacks both nitric oxide synthase (NOS)- and substance
P-immunoreactive nerve fibers when either the
or the
component
(leukemia inhibitory factor receptor-
) of the CNTFR is knocked out
in transgenic mice. Substance P is a marker for excitatory and NOS for
inhibitory motoneurons. Because the knockouts of CNTF or leukemia
inhibitory factor do not themselves produce the lethal effects of
deletion of the neuropoietic cytokine receptor, it is apparent that
neither is the endogenous ligand that is critical for the development
of enteric neurons. Both CNTF and leukemia inhibitory factor stimulate
the Janus kinase-signal transducer and activator of transcription
signal transduction pathway and promote the development in vitro of
neurons and glia from crest-derived cells immunoisolated from the fetal
gut. The effects of these factors on neuronal development are additive with those of NT-3.
The addition of enteric neurons to the developing bowel persists for a surprisingly long time. Although enteric neurons can be detected in the mouse foregut as early as E12, new neurons continue to be added at least through the first 3 wk of postnatal life (see Ref. 12 for references). Early and late-developing neurons, however, are not the same kind of cell. Although serotonergic neurons are all born very early (before E15), the first calcitonin gene-related peptide-containing neurons do not begin to be born until after the last serotonergic neuron has become postmitotic. Because of their precocious appearance, enteric serotonergic neurons coexist in primordial enteric ganglia with still-dividing neural precursors. In fact, electron micrographs have even revealed that synapses are present on the surfaces of dividing neuroblasts. For this reason, it has long been speculated that serotonin (5-HT) might not just be a neurotransmitter but, also in the primitive ENS, might be a growth factor that affects the development of late-arising enteric neurons. Recent observations have provided considerable evidence that this may well be the case (11). The 5-HT2B receptor has been found to be developmentally regulated in the fetal bowel. 5-HT2B expression can first be detected in the fetal mouse gut at E14. It peaks at E15-E16, when 5-HT2B expression can be detected in virtually all myenteric ganglia, and declines to adult levels (expression in fewer than one neuron in every four ganglia) by E18. When added to cells isolated at E15, the peak time of 5-HT2B expression, 5-HT strongly promotes the in vitro development of enteric neurons. This effect is blocked by the nonselective 5-HT2 antagonist, ritanserin, and mimicked by the 5-HT2 agonist, 2,5-dimethoxy-O-iodoamphetamine. The selective 5-HT2A antagonist, ketanserin, does not inhibit the 5-HT-induced development of enteric neurons. 5-HT appears to act by stimulating the phosphorylation and consequent nuclear translocation of mitogen-activated protein (MAP) kinase. The effect of 5-HT on MAP kinase in enteric neural precursors is also blocked by ritanserin. These observations imply that 5-HT can indeed act as a growth factor as well as a conventional neurotransmitter and that its developmental action is mediated by the transient and developmentally regulated expression of 5-HT2B receptors. An exciting potential implication of the discovery that 5-HT is a growth factor is that it might explain how the early experience-related activity of the ENS can sculpt its subsequent development. Put another way, the observation might provide a molecular basis for taking seriously, and understanding, the often-told anecdotes that "colicky" babies grow up to be adults with irritable bowel syndrome.
All of the growth-differentiation factors discussed to this point have in common that they are generally active agents. That is, they affect virtually the entire bowel. Another type of agent has recently been discovered. The peptide, ET-3, and its cognate receptor, ETB, have been found to play a critical role in ENS development (1, 15, 23); however, ET-3 is uniquely important, not to the development of ganglia in the whole bowel but to gangliogenesis in the terminal colon. The terminal colon is the sole region of the gut that becomes aganglionic when ET-3 or ETB are knocked out in mice or mutated in humans. In humans, this condition, known as Hirschsprung's disease or congenital megacolon, occurs in about 1 in 5,000 live births. Strains of mice also carry natural mutations in genes encoding ET-3 (lethal spotted, ls/ls) and ETB (piebald lethal sl/sl). When the relationship of ET-3-ETB to aganglionosis was first discovered, ET-3 was postulated to be an autocrine growth factor essential for the development of enteric neurons and melanocytes (mice with ET-3 or ETB defects are spotted). Unfortunately, this hypothesis, which treats ET-3 like any of the other growth factors that affect ENS development, does not account for the striking geographical limitation of the lesion that results from the loss of ET-3-ETB. Clearly, if ET-3-ETB were really essential for the development of enteric neurons (as a set), these cells would not be able to develop normally in the proximal bowel of ET-3-ETB-deficient individuals. The resulting disease would be more global, like that which results from deletions of GDNF or Ret, not a lesion that is restricted to the terminal colon.
Another problem with the autocrine growth factor hypothesis for the action of ET-3 is that the aganglionosis that results from ET-3-ETB mutations is not neural crest autonomous. For example, although crest-derived cells from exogenous sources can enter the normal mouse colon in vitro, no source of crest-derived cells can provide émigrés that enter the colons of ET-3-deficient mice (see Ref. 24 for references). Moreover, when segments of mouse gut are back transplanted between the neural tube and somites of quail embryos, quail crest-derived cells cannot enter the presumptive aganglionic bowel of ET-3-deficient mouse donors (25). In contrast, quail crest-derived cells have no difficulty in entering and passing through segments of normal mouse bowel. Finally, crest-derived cells that are genotypically ET-3- or ETB-defective will colonize the terminal bowel of aggregation chimeric mice as long as substantial numbers of the surrounding cells are normal (17, 18, 25). That means that the gut wall, as well as the crest-derived cells themselves, is probably abnormal in ET-3-ETB-defective individuals.
Recent studies have suggested that the role of
ET-3-ETB is not to promote but to
inhibit enteric neuronal development (14, 29). Certainly, that is the
effect of ET-3 and ETB agonists on
crest-derived cells immunoselected from the fetal mouse gut (29). The
ability of ET-3 to inhibit the in vitro development of enteric neurons
can be blocked by BQ-788, a specific
ETB antagonist. In contrast to its
effect on the development of enteric neurons, ET-3 enhances the
development of smooth muscle in cultures depleted of crest-derived
cells by negative immunoselection. By promoting smooth muscle
development and maturation, ET-3 downregulates the secretion of laminin
by smooth muscle precursors. This effect is important because
laminin-1, through an interaction of its 1-subunit with a receptor
[110-kDa laminin-1 binding protein (LBP110)] expressed by
crest-derived cells, is itself a powerful promoter of enteric neuronal
development (7). Furthermore, laminin-1 biosynthesis is upregulated and
laminin-1 accumulates in the terminal bowel of ET-3-deficient mice
(24).
The observations on the effects of ET-3 on enteric nerve and muscle development suggest that ET-3 might not affect the precursors of enteric neurons as a conventional growth factor but might act instead as a regulator of the timing of enteric neuronal development. The function of ET-3 might thus be to prevent the premature differentiation of neurons. When ET-3-ETB is lacking, conditions favor neuronal differentiation. A brake, ET-3, is missing and an accelerator, laminin-1, is present in excess. The last part of the bowel to be colonized is the terminal colon (19). Clearly, differentiation of neurons must be prevented from depleting the precursor pool before the entire bowel has been colonized. Crest-derived cells are motile and migratory; neurons are not. In addition, crest-derived cells multiply as they migrate, constantly expanding the precursor pool. Differentiation of neurons thus brings this expansion, as well as crest-derived cell migration, to a complete halt because neurons are postmitotic cells. To colonize the terminal bowel, vagal crest-derived cells have to migrate all the way down the gut, and sacral crest-derived cells, which do not start to migrate until long after the departure of their vagal counterparts from the neural crest, have to reach the colon. The ET-3-ETB deficiency-induced premature differentiation of neurons would thus be predicted to leave the terminal colon uncolonized and thus aganglionic. In fact, ectopic ganglia are found outside the terminal colon of ET-3-deficient mice (24). These ganglia are probably produced by sacral crest-derived cells that have differentiated and stopped migrating before their time.
Hirschsprung's disease is often associated with mutations in genes encoding GDNF-Ret (3, 16) or ET-3-ETB (9, 23). Mutations in Ret and ETB are much more frequently encountered than mutations in the two ligands. Because Ret and ETB are so fundamentally different in their actions on developing enteric neurons, it seems likely that, from the viewpoint of pathogenesis, there is not one Hirschsprung's disease but at least two forms of the condition. The final phenotype of each, congenital megacolon, is the same because the gut has only one way to manifest aganglionosis; nevertheless, two different mechanisms can be envisioned to cause the terminal colon to become aganglionic. One of these might be the result of a deficiency of GDNF-Ret that is not so severe as to cause the entire bowel to become aganglionic (as it is in GDNF or Ret knockout mice). Such a defect might lead to a precursor pool of crest-derived cells that is too small to colonize the whole gut. Whereas the complete loss of GDNF-Ret causes neurogenesis to fail totally in the entire bowel (below the rostral foregut), a submaximal deficiency of GDNF-Ret might cause the crest-derived precursor pool to expand insufficiently, so that the numbers of available cells produced from this pool are inadequate. The ability of GDNF to serve as a mitogen for crest-derived enteric neuronal precursors supports this idea (6). This mechanism for causing the terminal colon to become aganglionic is very different from that postulated to result from a deficiency of ET-3-ETB. In that case, as explained above, crest-derived cells are thought to differentiate prematurely, causing crest-derived precursors to cease dividing and migrating before the gut has been entirely colonized. As far as the terminal colon is concerned, the result is the same: it becomes aganglionic because the terminal colon is the last part of the bowel to be colonized by cells from the neural crest.
In summary, the development of the ENS can be understood as a symphony, complete with point and counterpoint. The point in the enteric music is the genetic background and lineages of crest-derived precursor cells. This theme plays out against the counterpoint of the effects of the microenvironment of the bowel wall. The result is the "multicultural" mélange of the mature ENS, an entity with neurons that displays extraordinary phenotypic diversity, complex microcircuits, and a brainlike ability to function independently of CNS control.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Neurological Disorders and Stroke Grants NS-12969 and NS-15547.
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FOOTNOTES |
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* Fifth in a series of invited articles on Neural Injury, Repair, and Adaptation in the GI Tract.
Address reprint requests to M. D. Gershon.
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