1 Department of Neurosciences, Case Western Reserve University, School Of
Medicine, Cleveland, OH 44106, USA
2 Department of Biological Sciences, Stanford University, Herrin Lab 150, 385
Serra Mall Stanford CA, 94305, USA
* Author for correspondence (e-mail: rhm3{at}po.cwru.edu)
Accepted 3 February 2003
![]() |
SUMMARY |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Oligodendrocyte precursor, Migration, Netrin, Chick
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Similar mechanisms may mediate oligodendrocyte precursor and immature
neuron migration. For example, radial neuronal migration occurs by association
with radial glial cells (Rakic,
1972). Likewise, in forebrain, subventricular-derived glial
precursors undergo radial migration
(Kakita and Goldman, 1999
) and
spinal cord oligodendrocyte precursors are found in close association with
radial glia (Hirano and Goldman,
1988
). Non-radial dispersal or tangential migration is influenced
by both chemoattractive and chemorepulsive cues
(Hatten, 2002
;
Tessier-Lavigne and Goodman,
1996
) such as netrins (Kennedy
et al., 1994
). Netrins can act as either chemoattractants or
chemorepellents for distinct populations of developing neurons
(Alcantara et al., 2000
;
Bloch-Gallego et al., 1999
)
depending on the specific combinations of receptors expressed
(Hong et al., 1999
;
Keleman and Dickson, 2001
).
Two distinct receptor families have been implicated in orchestrating cellular
responses to netrins (Ackerman et al.,
1997
; Chan et al.,
1996
; Leonardo et al.,
1997
), including DCC and UNC5. The migration of oligodendrocyte
precursors along the developing optic nerve from their origin in the floor of
the third ventricle is well established
(Ono et al., 1997
;
Small et al., 1987
) and has
been proposed to be mediated in part by chemorepulsion to netrin 1 secreted by
cells at the optic chiasm (Sugimoto et
al., 2001
), although netrin has also been suggested to be
chemoattractive for optic nerve oligodendrocyte precursors
(Spassky et al., 2002
). In the
spinal cord, netrin 1 is expressed during early embryogenesis in the floor
plate and ventral spinal cord (Kennedy et
al., 1994
). This localization is close to the origin of
oligodendrocyte precursors and suggests that netrin 1 might mediate spinal
cord oligodendrocyte precursor migration.
In the current study, we demonstrate that netrin 1 is expressed in the ventral spinal cord during the period of initial oligodendrocyte precursor emigration from their origin. In vitro, ventral spinal cord explants and netrin 1-secreting cells exert a chemorepulsive effect on migratory oligodendrocyte precursors and netrin 1 antagonizes PDGF chemoattraction on purified oligodendrocyte precursors in a chemotaxis assay. We further demonstrate that oligodendrocyte precursors express both DCC and UNC5, and inhibiting DCC signaling blocks the effects of netrin and ventral spinal cord explants. In slice preparations of embryonic chick spinal cord, migration of oligodendrocyte precursors to dorsal regions is inhibited by treatment with anti-DCC antibodies or recombinant netrin 1. These data suggest that netrin 1 provides a chemorepellent signal that results in the initial dispersal of oligodendrocyte precursors from their localized origin in the ventral spinal cord.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Chemotaxis assay
Chemotaxis assays were performed using a 48-well Boyden chamber (Neuro
probe, AP 48) (Tsai et al.,
2002) (Fig. 4D).
The lower chamber was flooded with PDGF (Sigma) and/or chick netrin 1 (R&D
systems) in F12 medium with N2 supplement (Gibco). Polycarbonate membranes
(Osmonics, 8 µM) were coated with poly-L-lysine and pan-purified
oligodendrocyte precursors from E7 chick spinal cords added to the upper
chamber with PDGF and/or netrin 1. After incubation for 20 hours at 37°C,
the membrane was fixed in methanol for 15 minutes and stained with ethidium
bromide (Molecular probes, 4 µM in PBS) for 8 minutes. Non-migrating cells
on the upper side of the membrane were removed and the number of migrating
cells counted. Experiments were performed in triplicate at least three times.
Three to four fields were counted under 20x magnification for each well,
and data are compared between groups by the Student's two-tailed
t-test (Microsoft Excel).
|
|
RT-PCR
Total RNA was extracted by RNeasy Mini kit (Qiagen) and was subjected to
reverse transcription for cDNA by Superscript first-strand synthesis system
(Gibco). The primers for DCC were 5'-TCA(C/T)CCTTCCAACCT(C/G)TATGC and
5'-TC(G/T)(A/G)AAGGT(A/G)TACATGGCTTC. The primers for UNC5-1 were
5'-GAGTCACCTTCCCACCTCTAC and 5'-AGACTGGCGATGATCTTTTG. The primers
for UNC5-2 were 5'-GTCTCAGGGTCTACTGTCTGG and
5'-GTGGTATCTTGAAGGCATAGG. The primers for neogenin were from published
results (Vielmetter et al.,
1994). The primers for chick netrin 1 were
5'-TACTGCAAGGAAGGCTTCTAC and 5'-TCATGTTGATCTTCAGCTTCC. The PCR
programs were run on DNA Engine thermocycler (MJ Research) using the following
program: 93°C for 30 seconds; 30 cycles of 93°C for 30 seconds,
56°C for 1 minute, 70°C for 1 minute; and the last step of 70°C
for 10 minutes. The DCC receptor products were digested with BsaHI
(NEB) for 1 hour at 37°C after RT-PCR amplification. The products were
analyzed on 1.2% agarose gel.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Separation of stage 29 chick spinal cord into dorsal (D), intermediate (I)
and ventral (V) regions (Fig.
1A) provided explants with different oligodendrogenic
characteristics. Dorsal explants contained virtually no oligodendrocyte
precursors or oligodendrocytes after 3 days in culture
(Warf et al., 1991)
(Fig. 1B,C). Intermediate
explants contained migratory oligodendrocyte precursors but no floor plate or
ventricular source. By contrast, ventral explants contained migratory
oligodendrocyte precursor cells as well as floor plate and a ventricular
source of new cells resulting in substantially more O4-positive cells
associated with ventral than intermediate explants
(Fig. 1D,E). The extent and
pattern of oligodendrocyte precursor migration differed between ventral and
intermediate explants. Ventral explants displayed more extensive but not
uniformly radial migration, while intermediate explants displayed more
uniformly radial migration. Ventrally derived O4-positive cells migrated
further (Fig. 1F) and covered a
larger area (Fig. 1G) than
intermediate derived cells.
The extensive migration of oligodendrocyte precursors from ventral explants may reflect ventral chemorepulsive activity. To test this, stage 29 intermediate explants were co-cultured with ventral explants to screen for directional cues. Intermediate-derived migrating oligodendrocyte precursors were repelled by ventral explants. In isolation, O4-positive cell migration from intermediate explants was uniformly radial (Fig. 2A). By contrast, when co-cultured in close proximity to ventral explants, the distribution of intermediate-derived migratory oligodendrocyte precursors was no longer uniformly radial (Fig. 2B), although the total number of O4-positive oligodendrocyte precursors was not significantly different, suggesting that co-culture did not influence oligodendrocyte precursor survival or proliferation. A greater number of oligodendrocyte precursors were present in regions of intermediate explants distal to than proximal to ventral explants (Fig. 2B). Quantification of the relative distribution of O4-positive cells revealed that 61±3% were distal to ventral explants while only 39±3% of O4-positive cells were proximal to ventral explants. This differential distribution of O4 cells was seen in greater than 70% of ventral-intermediate co-cultures (see Fig. 6E,F), although the magnitude varied depending on the proximity of the explants with a maximal effect at distances of less than 500 µm. The morphology of O4-positive cells proximal and distal to ventral explants was slightly different. Distally the majority of cells were unipolar with a leading process (Fig. 2D); however, cells oriented towards ventral explants had shorter or multiple processes (Fig. 2C). The observation that oligodendrocyte precursors oriented towards ventral explants did not demonstrate morphological characteristics of oriented growth may reflect two populations of oligodendrocyte precursors that differ in response to ventral-derived repulsive cues.
|
Netrin 1 is expressed at the spinal cord ventral midline during
oligodendrocyte precursor migration
Candidate guidance molecules for oligodendrocyte precursor dispersal
include netrin 1 that is expressed in the floor plate and ventral ventricular
zone earlier in development (Kennedy et
al., 1994). To determine whether netrin 1 expression was
maintained during the period of initial oligodendrocyte precursor emigration,
the presence of netrin 1 mRNA in stage 29 ventral spinal cords was examined by
RT-PCR. Using primers specific for chick netrin 1, mRNA was detected in
samples of ventral spinal cord and rostral CNS that was retained until E9
(Fig. 3). Control preparations
without reverse transcriptase did not amplify any detectable products (data
not shown). These data demonstrate the continued expression of netrin 1
between the stages 29 (E6) and E9 in the chick ventral spinal cord, a
developmental period that correlates with the initial migration of
oligodendrocyte precursors from the ventral ventricular domain.
|
Netrin chemorepulsion antagonizes the chemoattractive activity of PDGF. When PDGF and 100 ng/ml netrin 1 were added to the lower chamber, the numbers of migrating cells were significantly reduced compared with those seen with PDGF alone (Fig. 4E, 16.4±0.9 cells/field). In the presence of 400 ng/ml netrin 1, PDGF chemoattractive activity was almost totally abolished (Fig. 4E, 14.0±1.0) and the number of migrating cells was similar to that in controls (P=0.44). These observations indicate that netrin 1 is a bona fide chemorepellent for oligodendrocyte precursors and can antagonize PDGF chemoattraction.
Chick spinal cord oligodendrocyte precursors express netrin
receptors
Responses to netrin signaling are mediated through receptors including DCC,
UNC5 (Ackerman et al., 1997;
Chan et al., 1996
;
Leonardo et al., 1997
) and
neogenin. Chick spinal cord oligodendrocyte precursors express neogenin. Two
bands of appropriate sizes for neogenin were amplified by RT-PCR analyses from
pan-purified E10 and E12 O4-positive cells
(Fig. 5A) consistent with
alternative splicing (Vielmetter et al.,
1994
). To determine whether netrin receptors were expressed on the
surface of oligodendrocyte precursors, purified chick spinal cord O4-positive
cells (Fig. 5B) were labeled
with anti-neogenin (Fig. 5C)
and anti-DCC (Fig. 5D)
antibodies. Greater than 70% of cells were labeled with either antibody. To
confirm netrin receptor expression on migratory oligodendrocyte precursors the
expression of DCC and UNC5 was examined on A2B5 pan-purified immature rat
oligodendrocyte precursors. Immature A2B5-positive oligodendrocyte precursors
express all three netrin receptors detected by RT-PCR
(Fig. 5E). The products
amplified from DCC-specific primers were further analyzed by restriction
enzyme digestion (Fig. 5E)
resulting in two bands of predicted sizes. Consistent with these observations,
the majority of A2B5-positive cells purified from newborn rat spinal cord
expressed detectable cell surface DCC (Fig.
5F-H).
|
The chemorepulsive effect of netrin 1 on oligodendrocyte precursors
signals through a DCC-like receptor
To determine whether signaling through netrin receptors expressed by
oligodendrocyte precursors mediated netrin 1-stimulated chemorepulsion,
function-blocking anti-DCC and control antibodies were added to co-cultures.
The addition of anti-DCC antibodies neutralized the preferential migration of
oligodendrocyte precursors away from the netrin 1-positive cells and
re-established a uniformly radial pattern of migration. For example, in the
presence of anti-DCC antibodies, 49±3% of oligodendrocyte precursors
were located distal to the netrin 1-positive cells compared with 51±3%
of precursors located proximal to the netrin 1-positive cells
(Fig. 6B,E, P=0.2). By
contrast, addition of control IgG had little or no effect on the influence of
the netrin 1-positive cells on biasing oligodendrocyte precursor migration and
58% of the cells were located distally to the netrin 1-positive cells
(Fig. 6E, n=21). These
observations implicate a DCC-like receptor in mediating netrin 1 guidance of
migrating oligodendrocyte precursors.
To determine whether the chemorepulsive effect of ventral explants on oligodendrocyte precursors was dependent on netrin 1 signaling through DCC receptors, co-cultures of ventral and intermediate explants were grown in the presence of function blocking anti-DCC and control antibodies. Addition of anti-DCC antibodies neutralized the chemorepulsive cues from ventral explants and re-established a uniformly radial migration from intermediate explants. For example in the presence of anti-DCC, a similar distribution of oligodendrocyte precursors was seen on either side with 48±2% of O4-positive cells located distal and 52±2% located proximal to the ventral explants (Fig. 6C,E). By contrast, chemorepulsive cues from ventral explants were not inhibited by control antibodies (Fig. 6E) with 60±5% of oligodendrocyte precursors located distal and 40±5% located proximal (n=12) to the ventral explants. Taken together, these data demonstrates the ventral spinal cord-derived chemorepulsion is dependent on DCC signaling and is consistent with netrin 1 guiding the initial dispersal of spinal cord oligodendrocyte precursors from the ventral ventricular zone.
Inhibition of netrin signaling blocks the dispersal of
oligodendrocyte precursors in chick spinal cord slices
To determine whether netrin 1 signaling mediates the dispersal of
oligodendrocyte precursors through the neuropil of the developing spinal cord,
the effects of function-blocking anti-DCC antibody on the dispersal of
oligodendrocyte precursors in slice preparations of chick spinal cord were
assessed. The normal ventral to dorsal migration of spinal cord
oligodendrocyte precursors is conserved in embryonic slice preparations.
Oligodendrocyte precursors labeled with mAb O4 are first detected around stage
28/29 and stage 28 slices labeled with mAb O4 one hour after dissection showed
trace labeling in the ventral ventricular region
(Fig. 7A). After 24 hours in
culture, the distribution of oligodendrocyte precursors was predominately
ventral (Fig. 7B), whereas
after 48 hours many O4-positive cells demonstrated extensive migration to the
dorsal spinal cord (Fig. 7C)
where they had a characteristic unipolar morphology
(Fig. 7D). In slice cultures
grown in the presence of anti-DCC antibody (10 µg/ml) for 48 hours, the
ventral to dorsal migration of oligodendrocyte precursors was significantly
inhibited and the majority of oligodendrocyte precursors had smaller cell
bodies localized close to the ventral ventricular zone or ventral lateral pial
surface (Fig. 7E,F)
(Table 1). For example,
comparison of the relative number of O4-positive cells in dorsal, intermediate
and ventral spinal cord showed that in controls 19±2% of cells were
located in dorsal regions, whereas in anti-DCC treated slices this was reduced
to 9±2%. A similar perturbation in the pattern of oligodendrocyte
precursor migration was seen when slices were grown in the presence of
exogenously added netrin 1 (Fig.
7G). For example, the proportion of cells in dorsal spinal cord
was reduced to 11±2% in the presence of 500 ng/ml netrin 1. The total
number of O4-positive oligodendrocyte precursor cells in slices cultured with
anti-DCC antibody (123.0±13.8 cells/slice) or netrin 1
(125.0±12.8) were similar to the control (160.6±14.0). The
effects on oligodendrocyte precursor migration were specific for netrin
signaling. Non-immune mouse IgG did not significantly affect the distribution
of oligodendrocyte precursors (Fig.
7H) nor did addition of anti-prion antibodies
(Fig. 7I) that labeled the
majority of chick O4-positive cells (data not shown). Antibodies to neural
cell-adhesion molecule (NCAM) did result in a perturbation of the pattern of
migration resulting in a more radial-lateral pattern
(Fig. 7J) but did not mimic the
migration inhibiting effects of anti-DCC or netrin 1. The influence of
anti-NCAM antibodies is consistent with in vitro data, suggesting that
NCAM-associated polysialic acid (PSA) is important in oligodendrocyte
precursor migration (Decker et al.,
2000; Hughson et al.,
1998
). The dependence of oligodendrocyte precursor dispersal on
netrin was transient. When slices were prepared from stage 31 embryos
O4-positive cells were more dispersed (Fig.
7K) than at stage 28 after 24 hours (compare
Fig. 7B with 7K). After 48
hours in vitro, neither anti-DCC antibody
(Fig. 7L,M) nor addition of
netrin 1 (Fig. 7N,O) had a
significant effect on the migration of oligodendrocyte precursors.
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Myelination of the spinal cord is crucially dependent on long-distance
migration of oligodendrocyte precursors. The founder cells of the lineage
arise in a ventrally located domain as a result of local sonic hedgehog
signaling (Orentas and Miller,
1996; Pringle et al.,
1996
), although their progenies are dispersed throughout the
entire spinal cord and eventually concentrated in peripheral white matter.
While classical contact inhibition of motility
(Heaysman and Pegrum, 1973
)
would tend to dissipate cells from a high density source, it is unlikely to
contribute to the spread of spinal cord oligodendrocyte precursors because it
would be relatively slow, not provide direction for isolated cells and is not
demonstrated by oligodendrocyte precursors in vitro (Tsai and Miller,
unpublished). By analogy with neuronal cell migration, radial glia may
facilitate later migration of oligodendrocyte precursors in white matter where
they are closely aligned with radial glia
(Hirano and Goldman, 1988
).
The pattern of initial dispersal and ventral to dorsal oligodendrocyte
precursor migration is not, however, consistent with the distribution of
radial glia in the spinal cord (Noll and
Miller, 1993
; Ono et al.,
1995
), suggesting these cells do not influence initial
oligodendrocyte precursor dispersal. Rather, the pattern of oligodendrocyte
precursor dispersal suggests a repulsive cue regardless of cellular
substrate.
Netrin 1 is essential for the initial dispersal of spinal cord
oligodendrocyte precursors. In the spinal cord, the netrins are pivotal
guidance molecules for dorsoventral patterning mediating both attraction and
repulsion in neurons (Wadsworth,
2002) and netrin 1 appears to selectively affect the dorsal and
lateral migration of spinal cord oligodendrocyte precursors. In slice
preparations grown in the presence of anti-DCC or exogenous netrin 1,
ventrally migrating oligodendrocyte precursors appear to be unaffected, while
cells migrating laterally and dorsally are severely inhibited. This
differential sensitivity to netrin signaling may reflect the expression of
different receptor combinations (Hong et
al., 1999
; Keleman and
Dickson, 2001
) on subsets of oligodendrocyte precursors, different
modes of migration or the use of alternative substrate. It seems likely,
however, that there is heterogeneity among ventrally derived spinal cord
oligodendrocyte precursors. For example, although the majority of
oligodendrocyte precursors emerge from the pMN domain are Nkx2.2 and Olig2
positive (Zhou et al., 2001
),
a subset are proposed to derive from Nkx2.2-positive/Olig2-negative cells
(Soula et al., 2001
). It is
possible that cells destined to the ventral regions of the spinal cord are
derived from a similar subset of ventricular cells. Alternatively, spinal cord
oligodendrocyte precursors may intrinsically be a homogenous cell population
whose responses to guidance molecules such as netrin 1 are modulated by local
environmental signals, thereby allowing a subset of cells to escape netrin 1
repulsion.
The response of oligodendrocyte precursors to netrin 1 is temporally
regulated. The initial dispersal from the ventricular zone is blocked by
addition of anti-DCC or netrin 1. By contrast, later in development, similar
treatments appear to have little effect. This lack of effect may reflect
either a maturation event in oligodendrocyte precursors or an alteration in
guidance cues. It seems likely that the guidance of oligodendrocyte precursors
to appropriate domains of the spinal cord will involve multiple guidance cues
such as semaphorin 3A (Sema3A) and slit. The chemorepulsive cue slit is
expressed in ventral spinal cord (Brose et
al., 1999; Li et al.,
1999
; Yuan et al.,
1999
), as is Sema3A (Luo et
al., 1995
; Puschel et al.,
1995
). Non-migratory mature oligodendrocytes express the Sema3A
receptor neuropilin 1 and retract established processes in response to Sema3A
(Ricard et al., 2001
), while
some optic nerve glial precursors are repelled by Sema3A
(Spassky et al., 2002
;
Sugimoto et al., 2001
).
Neuropilin, the Sema3A receptor, is functionally associated with adhesion
molecules, including NCAM (Castellani et
al., 2000
). The embryonic form of NCAM (PSA-NCAM) modulates
oligodendrocyte precursor migration in vitro
(Decker et al., 2000
) and
alters the pattern of oligodendrocyte precursor migration in spinal cord
slices. This altered migratory pattern may reflect disruption of Sema3A
guidance. Neither Sema3A nor slit appears to mediate initial oligodendrocyte
precursor dispersal; however, as this is inhibited by blocking netrin 1.
The guidance of migratory oligodendrocyte precursors by diffusible cues is
not restricted to the spinal cord. In the optic nerve, glial precursors
migrate from the chiasm to the retina (Ono
et al., 1997; Small et al.,
1987
) in response to chemorepulsive cues from the chiasm
(Spassky et al., 2002
;
Sugimoto et al., 2001
). In
postnatal rat optic nerve, netrin 1 provided chemorepulsion to NG2-positive
cells, considered to be oligodendrocyte precursors
(Nishiyama et al., 1996
),
while Sema3A was chemorepulsive to an unidentified class of cells
(Sugimoto et al., 2001
). By
contrast, in embryonic mouse optic nerve cultures, netrin 1 was
chemoattractive for A2B5-positive cells while Sema3A was chemorepulsive
(Spassky et al., 2002
). The
differential responses in the two systems might represent species differences,
analyses of different cell populations or experimental conditions because
directionality is dependent on receptor usage and signal transduction pathways
(Hong et al., 1999
;
Ming et al., 1997
). The
present study indicates that netrin 1 exerts a direct chemorepulsive effect on
unambiguously identified purified chick spinal cord oligodendrocyte
precursors. Not only is netrin 1 chemorepulsive, but it can also negate PDGF
chemoattraction.
Functional studies indicate that a DCC-like molecule is crucial in
mediating the chemorepulsion of oligodendrocyte precursors by netrin 1. In
rodent neurons, both DCC and UNC5 are required for netrin 1 to exert repulsive
activity (Hong et al., 1999).
Consistent with this notion, oligodendrocyte precursors from the rat spinal
cord express both UNC5 and DCC receptors and at least in the optic nerve these
cells are repelled by netrin 1 (Sugimoto
et al., 2001
). The expression of UNC5 on chick oligodendrocyte
precursors is unclear; however, they do express neogenin another member of the
DCC family. It seems likely that netrin-induced chemorepulsion in
oligodendrocyte precursors is mediated by similar modular receptors such as
DCC and/or neogenin and an UNC5-like receptor. At high netrin concentrations,
UNC5 receptors alone may mediate chemorepulsion with DCC required at lower
concentrations over a longer distance
(Keleman and Dickson, 2001
).
It is possible that expression of DCC on oligodendrocyte precursors allows
them to respond to a broad spectrum of netrin concentrations and thereby
ensure their widespread dissemination throughout the cord. In contrast to
other systems where signaling through DCC promotes cell survival
(Llambi et al., 2001
;
Mehlen et al., 1998
) and in
the absence of ligand, DCC receptors trigger the apoptosis pathway
(Bloch-Gallego et al., 1999
),
oligodendrocyte precursors do not appear to depend on DCC for survival. In the
developing mouse spinal cord, the normal development of oligodendrocytes
appear to be at least partially dependent on netrin and DCC. Recent studies
(Jarjour et al., 2003
)
demonstrate that the normal ventral-to-dorsal migration of oligodendrocyte
precursor is impaired in the spinal cord of netrin 1 and DCC mutants, while
the number of newly differentiated oligodendrocytes is dramatically reduced in
the spinal cord of netrin 1 mutant animals
(Tsai and Miller, 2002
)
suggesting that netrin-mediated precursor dispersal is critical for spinal
cord oligodendrogenesis. In addition, the finding that netrin 1 directs the
migration of oligodendrocyte precursors from the ventral ventricular zone
provides an attractive explanation for that aberrant patterning of
oligodendrocytes in the spinal cord of CXCR2-null animals in which white
matter is present as a thin layer with oligodendrocytes residing close to the
pial surface. The chemokine CXCL1, the ligand for CXCR2 acts as a rapid and
reversible stop signal for migrating spinal cord oligodendrocyte precursors
(Tsai et al., 2002
). In
developing spinal cord, CXCL1 is expressed by white matter astrocytes in a
tightly regulated pattern. Oligodendrocyte precursors lacking CXCR2 are
refractory to CXCL1 and thus continue to migrate away from the ventricular
zone under the influence of netrin 1 until they reach the outer limits or pial
surface of the spinal cord. Such a combinatorial signaling system is likely to
be responsible for patterning oligodendrocyte localization throughout the
developing vertebrate CNS.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ackerman, S. L., Kozak, L. P., Przyborski, S. A., Rund, L. A., Boyer, B. B. and Knowles, B. B. (1997). The mouse rostral cerebellar malformation gene encodes an UNC-5-like protein. Nature 386,838 -842.[CrossRef][Medline]
Alcantara, S., Ruiz, M., de Castro, F., Soriano, E. and Sotelo,
C. (2000). Netrin 1 acts as an attractive or as a repulsive
cue for distinct migrating neurons during the development of the cerebellar
system. Development 127,1359
-1372.
Armstrong, R. C., Harvath, L. and Dubois-Dalcq, M. E. (1990). Type 1 astrocytes and oligodendrocyte-type 2 astrocyte glial progenitors migrate toward distinct molecules. J. Neurosci. Res. 27,400 -407.[Medline]
Barres, B. A., Hart, I. K., Coles, H. S., Burne, J. F., Voyvodic, J. T., Richardson, W. D. and Raff, M. C. (1992). Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70, 31-46.[Medline]
Bloch-Gallego, E., Ezan, F., Tessier-Lavigne, M. and Sotelo,
C. (1999). Floor plate and netrin-1 are involved in the
migration and survival of inferior olivary neurons. J.
Neurosci. 19,4407
-4420.
Brose, K., Bland, K. S., Wang, K. H., Arnott, D., Henzel, W., Goodman, C. S., Tessier-Lavigne, M. and Kidd, T. (1999). Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96,795 -806.[Medline]
Castellani, V., Chedotal, A., Schachner, M., Faivre-Sarrailh, C. and Rougon, G. (2000). Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27,237 -249.[Medline]
Chan, S. S., Zheng, H., Su, M. W., Wilk, R., Killeen, M. T., Hedgecock, E. M. and Culotti, J. G. (1996). UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 87,187 -195.[Medline]
Decker, L., Avellana-Adalid, V., Nait-Oumesmar, B., Durbec, P. and Baron-Van Evercooren, A. (2000). Oligodendrocyte precursor migration and differentiation: combined effects of PSA residues, growth factors, and substrates. Mol. Cell. Neurosci. 16,422 -439.[CrossRef][Medline]
Frelinger, A. L., 3rd and Rutishauser, U. (1986). Topography of N-CAM structural and functional determinants. II. Placement of monoclonal antibody epitopes. J. Cell Biol. 103,1729 -1737.[Abstract]
Hamburger, V. and Hamilton, H. (1951). A series of normal stages in the development of the chick embryo. J. Morphol. 88,49 -92.
Harvath, L., Falk, W. and Leonard, E. J. (1980). Rapid quantitation of neutrophil chemotaxis: use of a polyvinylpyrrolidone-free polycarbonate membrane in a multiwell assembly. J. Immunol. Methods 37,39 -45.[CrossRef][Medline]
Hatten, M. E. (2002). New directions in
neuronal migration. Science
297,1660
-1663.
Heaysman, J. E. and Pegrum, S. M. (1973). Early contacts between fibroblasts. An ultrastructural study. Exp. Cell Res. 78,71 -78.[Medline]
Hirano, M. and Goldman, J. E. (1988). Gliogenesis in rat spinal cord: evidence for origin of astrocytes and oligodendrocytes from radial precursors. J. Neurosci. Res. 21,155 -167.[Medline]
Hong, K., Hinck, L., Nishiyama, M., Poo, M. M., Tessier-Lavigne, M. and Stein, E. (1999). A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell 97,927 -941.[Medline]
Hughson, E., Dowler, S., Geall, K., Johnson, G. and Rumsby, M. (1998). Rat oligodendrocyte O-2A precursor cells and the CG-4 oligodendrocyte precursor cell line express cadherins, beta-catenin and the neural cell adhesion molecule, NCAM. Neurosci. Lett. 251,157 -160.[CrossRef][Medline]
Jarjour, A. A., Manitt, C., Moore, S. W., Thompson, K. M., Yuh, S. J. and Kennedy, T. E. (2003). Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord. J. Neurosci. (in press)
Kakita, A. and Goldman, J. E. (1999). Patterns and dynamics of SVZ cell migration in the postnatal forebrain: monitoring living progenitors in slice preparations. Neuron 23,461 -472.[Medline]
Keleman, K. and Dickson, B. J. (2001). Short- and long-range repulsion by the Drosophila unc5 netrin receptor. Neuron 32,605 -617.[Medline]
Kennedy, T. E., Serafini, T., de la Torre, J. R. and Tessier-Lavigne, M. (1994). Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78,425 -435.[Medline]
Leonardo, E. D., Hinck, L., Masu, M., Keino-Masu, K., Ackerman, S. L. and Tessier-Lavigne, M. (1997). Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature 386,833 -838.[CrossRef][Medline]
Li, H. S., Chen, J. H., Wu, W., Fagaly, T., Zhou, L., Yuan, W., Dupuis, S., Jiang, Z. H., Nash, W., Gick, C. et al. (1999). Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. Cell 96,807 -818.[Medline]
Llambi, F., Causeret, F., Bloch-Gallego, E. and Mehlen, P.
(2001). Netrin-1 acts as a survival factor via its receptors
UNC5H and DCC. EMBO J.
20,2715
-2722.
Lu, Q. R., Yuk, D., Alberta, J. A., Zhu, Z., Pawlitzky, I., Chan, J., McMahon, A. P., Stiles, C. D. and Rowitch, D. H. (2000). Sonic hedgehogregulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25,317 -329.[Medline]
Luo, Y., Shepherd, I., Li, J., Renzi, M. J., Chang, S. and Raper, J. A. (1995). A family of molecules related to collapsin in the embryonic chick nervous system. Neuron 14,1131 -1140.[Medline]
Mehlen, P., Rabizadeh, S., Snipas, S. J., Assa-Munt, N., Salvesen, G. S. and Bredesen, D. E. (1998). The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395,801 -804.[CrossRef][Medline]
Miller, R. H. (1996). Oligodendrocyte origins. Trends Neurosci. 19,92 -96.[CrossRef][Medline]
Miller, R. H., Payne, J., Milner, L., Zhang, H. and Orentas, D. M. (1997). Spinal cord oligodendrocytes develop from a limited number of migratory highly proliferative precursors. J. Neurosci. Res. 50,157 -168.[CrossRef][Medline]
Ming, G. L., Song, H. J., Berninger, B., Holt, C. E., Tessier-Lavigne, M. and Poo, M. M. (1997). cAMP-dependent growth cone guidance by netrin-1. Neuron 19,1225 -1235.[Medline]
Nishiyama, A., Lin, X. H., Giese, N., Heldin, C. H. and Stallcup, W. B. (1996). Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain. J. Neurosci. Res. 43,299 -314.[CrossRef][Medline]
Noble, M., Murray, K., Stroobant, P., Waterfield, M. D. and Riddle, P. (1988). Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature 333,560 -562.[CrossRef][Medline]
Noll, E. and Miller, R. H. (1993).
Oligodendrocyte precursors originate at the ventral ventricular zone dorsal to
the ventral midline region in the embryonic rat spinal cord.
Development 118,563
-573.
Ono, K., Bansal, R., Payne, J., Rutishauser, U. and Miller, R.
H. (1995). Early development and dispersal of oligodendrocyte
precursors in the embryonic chick spinal cord.
Development 121,1743
-1754.
Ono, K., Yasui, Y., Rutishauser, U. and Miller, R. H. (1997). Focal ventricular origin and migration of oligodendrocyte precursors into the chick optic nerve. Neuron 19,283 -292.[Medline]
Orentas, D. M. and Miller, R. H. (1996). The origin of spinal cord oligodendrocytes is dependent on local influences from the notochord. Dev. Biol. 177, 43-53.[CrossRef][Medline]
Pringle, N., Collarini, E. J., Mosley, M. J., Heldin, C. H., Westermark, B. and Richardson, W. D. (1989). PDGF A chain homodimers drive proliferation of bipotential (O-2A) glial progenitor cells in the developing rat optic nerve. EMBO J. 8,1049 -1056.[Abstract]
Pringle, N. P., Mudhar, H. S., Collarini, E. J. and Richardson, W. D. (1992). PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha-receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage. Development 115,535 -551.[Abstract]
Pringle, N. P., Yu, W. P., Guthrie, S., Roelink, H., Lumsden, A., Peterson, A. C. and Richardson, W. D. (1996). Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog. Dev. Biol. 177,30 -42.[CrossRef][Medline]
Puschel, A. W., Adams, R. H. and Betz, H. (1995). Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension. Neuron 14,941 -948.[Medline]
Raff, M. C., Mirsky, R., Fields, K. L., Lisak, R. P., Dorfman, S. H., Silberberg, D. H., Gregson, N. A., Leibowitz, S. and Kennedy, M. C. (1978). Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture. Nature 274,813 -816.[Medline]
Rakic, P. (1972). Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145,61 -83.[Medline]
Ricard, D., Rogemond, V., Charrier, E., Aguera, M., Bagnard, D.,
Belin, M. F., Thomasset, N. and Honnorat, J. (2001).
Isolation and expression pattern of human Unc-33-like phosphoprotein
6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with
Ulip2/CRMP2 in Sema3a-sensitive oligodendrocytes. J.
Neurosci. 21,7203
-7214.
Rowitch, D. H., Lu, Q. R., Kessaris, N. and Richardson, W. D. (2002). An `oligarchy' rules neural development. Trends Neurosci. 25,417 -422.[CrossRef][Medline]
Serafini, T., Colamarino, S. A., Leonardo, E. D., Wang, H., Beddington, R., Skarnes, W. C. and Tessier-Lavigne, M. (1996). Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87,1001 -1014.[Medline]
Small, R. K., Riddle, P. and Noble, M. (1987). Evidence for migration of oligodendrocyte-type-2 astrocyte progenitor cells into the developing rat optic nerve. Nature 328,155 -157.[CrossRef][Medline]
Soula, C., Danesin, C., Kan, P., Grob, M., Poncet, C. and
Cochard, P. (2001). Distinct sites of origin of
oligodendrocytes and somatic motoneurons in the chick spinal cord:
oligodendrocytes arise from Nkx2.2-expressing progenitors by a Shh-dependent
mechanism. Development
128,1369
-1379.
Spassky, N., de Castro, F., le Bras, B., Heydon, K.,
Queraud-LeSaux, F., Bloch-Gallego, E., Chedotal, A., Zalc, B. and
Thomas, J. L. (2002). Directional guidance of
oligodendroglial migration by class 3 semaphorins and netrin-1. J.
Neurosci. 22,5992
-6004.
Sugimoto, Y., Taniguchi, M., Yagi, T., Akagi, Y., Nojyo, Y. and
Tamamaki, N. (2001). Guidance of glial precursor cell
migration by secreted cues in the developing optic nerve.
Development 128,3321
-3330.
Tessier-Lavigne, M. and Goodman, C. S. (1996).
The molecular biology of axon guidance. Science
274,1123
-1133.
Tsai, H. H. and Miller, R. H. (2002). Altered spinal cord oligodendrocyte precursor development in netrin mutant mice. Soc. Neurosci. Abstr. 32, 128.16.
Tsai, H. H., Frost, E., To, V., Robinson, S., ffrench-Constant, C., Geertman, R., Ransohoff, R. M. and Miller, R. H. (2002). The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110,373 -383.[Medline]
Varela-Echavarria, A., Tucker, A., Puschel, A. W. and Guthrie, S. (1997). Motor axon subpopulations respond differentially to the chemorepellents netrin-1 and semaphorin D. Neuron 18,193 -207.[Medline]
Vielmetter, J., Kayyem, J. F., Roman, J. M. and Dreyer, W. J. (1994). Neogenin, an avian cell surface protein expressed during terminal neuronal differentiation, is closely related to the human tumor suppressor molecule deleted in colorectal cancer. J. Cell Biol. 127,2009 -2020.[Abstract]
Wadsworth, W. G. (2002). Moving around in a worm: netrin UNC-6 and circumferential axon guidance in C. elegans. Trends Neurosci. 25,423 -429.[CrossRef][Medline]
Warf, B. C., Fok-Seang, J. and Miller, R. H. (1991). Evidence for the ventral origin of oligodendrocyte precursors in the rat spinal cord. J. Neurosci. 11,2477 -2488.[Abstract]
Warrington, A. E., Barbarese, E. and Pfeiffer, S. E. (1993). Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts. J. Neurosci. Res. 34, 1-13.[Medline]
Watanabe, M., Frelinger, A. L., 3rd and Rutishauser, U. (1986). Topography of N-CAM structural and functional determinants. I. Classification of monoclonal antibody epitopes. J. Cell Biol. 103,1721 -1727.[Abstract]
Yuan, W., Zhou, L., Chen, J. H., Wu, J. Y., Rao, Y. and Ornitz, D. M. (1999). The mouse SLIT family: secreted ligands for ROBO expressed in patterns that suggest a role in morphogenesis and axon guidance. Dev. Biol. 212,290 -306.[CrossRef][Medline]
Zhou, Q., Wang, S. and Anderson, D. J. (2000). Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25,331 -343.[Medline]
Zhou, Q., Choi, G. and Anderson, D. J. (2001). The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2. Neuron 31,791 -807.[Medline]
Related articles in Development: