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The Journal of Neuroscience, August 1, 2000, 20(15):5792-5801
Netrin-1 Promotes Thalamic Axon Growth and Is Required for Proper Development of the Thalamocortical Projection
Janet E. Braisted1, Susan M. Catalano2, Robert Stimac1, Timothy E. Kennedy3, Marc Tessier-Lavigne3, Carla J. Shatz2, and Dennis D. M. O'Leary1 1 Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037, 2 Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, and 3 Departments of Anatomy and of Biochemistry and Biophysics, University of California, San Francisco, California 94143
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
The thalamocortical axon (TCA) projection originates in dorsal thalamus, conveys sensory input to the neocortex, and has a critical role in cortical development. We show that the secreted axon guidance molecule netrin-1 acts in vitro as an attractant and growth promoter for dorsal thalamic axons and is required for the proper development of the TCA projection in vivo. As TCAs approach the hypothalamus, they turn laterally into the ventral telencephalon and extend toward the cortex through a population of netrin-1-expressing cells. DCC and neogenin, receptors implicated in mediating the attractant effects of netrin-1, are expressed in dorsal thalamus, whereas unc5h2 and unc5h3, netrin-1 receptors implicated in repulsion, are not. In vitro, dorsal thalamic axons show biased growth toward a source of netrin-1, which can be abolished by netrin-1-blocking antibodies. Netrin-1 also enhances overall axon outgrowth from explants of dorsal thalamus. The biased growth of dorsal thalamic axons toward the internal capsule zone of ventral telencephalic explants is attenuated, but not significantly, by netrin-1-blocking antibodies, suggesting that it releases another attractant activity for TCAs in addition to netrin-1. Analyses of netrin-1
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Key words: axon guidance; chemoattraction; DCC; dorsal thalamus; internal capsule; neocortex; neogenin; striatum; Unc5 homologs
INTRODUCTION
One of the major axon tracts in the mammalian forebrain is the internal capsule (IC), which is the path of cortical efferent axons and thalamocortical axons (TCAs) through the ventral telencephalon. TCAs originate in dorsal thalamus and relay sensory information from the periphery to the neocortex (Jones, 1985
). In addition, TCAs are required for the proper differentiation of cortical layers and areas (Chenn et al., 1997
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Figure 1. TCA pathway. Schematic of a coronal section of mouse brain showing the mature TCA projection and relevant brain structures. TCAs (black), originating in dorsal thalamus (dTh; light gray), project ventrally along the lateral aspect of ventral thalamus (vTh). As they approach the hypothalamus (Hy), TCAs make a sharp lateral turn and extend dorsolaterally through the striatum (St) toward neocortex (Ctx). TCAs are compactly bundled along the proximal portion of their path, but fan-out into numerous fascicles as they extend dorsolaterally through the striatum. As TCAs extend through the Ctx, their path becomes centered on the subplate layer (SP), and branches of TCAs (medium gray) extend into and innervate the cortical plate (CP). TCAs, together with the oppositely extending corticothalamic axons, form the internal capsule (ic), the major axon tract for cortical input and output projections. Dashed lines indicate the approximate borders between the ventral thalamus and hypothalamus, diencephalon and striatum, and striatum and neocortex.
Although the mechanisms directing the pathfinding of TCAs to the neocortex are not well understood, recent studies suggest that a variety of spatially and functionally distinct cues are involved. Contact-mediated cues have been implicated in the guidance of TCAs into and through the ICZ. Although the details differ between them, axon tracing studies in hamster (Metin and Godement, 1996
The axon chemoattractant netrin-1 (Kennedy et al., 1994
MATERIALS AND METHODS
Animals. ICR mice from embryonic day 13.5 (E13.5)-E14.5 were obtained from timed-pregnant females (Harlan Sprague Dawley, Indianapolis, IN). Embryos were staged according to Butler and Juurlink (1987)
In situ hybridization. In situ hybridizations of 20 µm cryosections were performed as previously described (Tuttle et al., 1999
Preparation of explants. Embryos were removed from anesthetized timed-pregnant mice (E13.5-E14.5) and rats (E17-E18). To isolate the ICZ and dorsal thalamus, embryonic mouse brains were removed, embedded in 3% low melting point agar (Seaplaque FMC Bioproducts) in L-15 medium supplemented with 0.6% glucose (Sigma, St. Louis, MO; L15-glucose), and sectioned coronally at 200 µm using a vibratome. Sections where the IC bridges the diencephalon and ICZ were collected, and the neocortex and diencephalon were removed. This piece served as the ICZ explant (Fig. 2A, boxed area). Dorsal thalamus was isolated from the remaining diencephalic pieces, as well as from more caudal sections, by making two cuts
one through the external medullary lamina/medial lemniscus to remove the ventral thalamus and hypothalamus and a second dorsal cut to remove the epithalamus. The resulting piece of tissue was bisected to yield two explants
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Figure 2. Expression of netrin-1 and netrin receptors in relation to the TCA projection. Coronal sections of E14.5 (A, A') and E13.5 (B-E) mouse brains showing netrin-1 (A, A', B), DCC (C), neogenin (D), and unc5h3 (E) expression detected with digoxigenin-labeled riboprobes. Dorsal is up. Lateral is to the right in A' and B. A, At E14.5, netrin-1 expression is detected in the differentiating mantle zone of the ICZ, as well as in the overlying ventricular zone (small arrow). Netrin-1 is also expressed in the medial part of dorsal thalamus (dTh; small arrowhead), hippocampus (Hi; large arrow), and the hypothalamic (Hy) ventricular zone (large arrowhead). A', Higher magnification of boxed area in A. This is the region used in coculture experiments in Figure 7 (see Materials and Methods). Netrin-1-expressing cells are present in the ICZ (arrows), intermingled with fascicles of TCAs in the internal capsule (ic). B, At E13.5, netrin-1 is expressed in the ICZ, in cells within (small arrow) and surrounding (large arrow) the internal capsule (ic). Expression is also detected in the overlying ventricular zone of the ganglionic eminence (arrowhead). C, DCC expression is detected in the ventricular zone (small arrow) and differentiating mantle zone (large arrow) of dorsal thalamus, and in cells at the dorsal thalamic-ventral thalamic border (arrowhead). The expression within the mantle zone corresponds to the location of the ventral posterior thalamic nucleus (VB). Asterisk indicates high expression in medial habenula. D, Neogenin is expressed in medial dorsal thalamus (arrow). E, Unc5h3 is expressed in the lateral dorsal part of ventral thalamus (arrow), but not in dorsal thalamus. Scale bars: A, 500 µm; A', B, C, 250 µm (bar in C also applies to D, E).
Aggregates of netrin-1-expressing cells. A netrin-1-secreting 293-EBNA cell line was used (Shirasaki et al., 1996
Collagen gel cocultures. Collagen was prepared from either adult rat tails or 8-10 cm tails from juvenile rats. Cocultures were set up as follows: 900 µl of collagen solution was mixed with 100 µl of 10× MEM, and 11-18 µl of a 7.5% solution of sodium bicarbonate. Twenty-five microliters of collagen was pipetted onto the bottom of four well dishes (Nunc, Roskilde, Denmark) and allowed to gel. Explants were then placed onto this base, and 75 µl of collagen was added on top. Dorsal thalamic explants and test explants (floor plate or ICZ), or 293 cell aggregates, were positioned ~150-300 µm apart. Dorsal thalamic explants were placed adjacent to the medial aspect of the ICZ explants. The orientation of the explant relative to the test explant or 293 cell aggregates was random. Growth medium (GM; 500 µl of DMEM/F-12 containing 0.1% penicillin-streptomycin, 0.6% D-glucose, 2 mM glutamine, and 5% rat serum) was then added. Explants were cultured in a humidified, 37°C, CO2 incubator.
Analysis of axon outgrowth in cocultures. After 1.5 d in vitro, dorsal thalamic axon outgrowth was scored and assigned to one of three categories; explants that had more axon outgrowth either (1)toward or (2) away from the test explant or 293 cell aggregates, or (3) explants that had similar amounts of axon outgrowth on both of these sides and were therefore scored as "symmetric". For dorsal thalamus cultured alone, the near side of the dish was arbitrarily designated "toward" and the far of the dish "away." Cultures were scored blind, and data was analyzed statistically using the
2 test.
Analysis of axon outgrowth in response to soluble recombinant netrin-1. Dorsal thalamic explants were placed in collagen gels (see above). At the time of plating, purified, recombinant netrin-1 protein produced in 293 cells (Serafini et al., 1994
Function blocking experiments. At the time of plating, affinity-purified rabbit antibodies raised against domains VI and V of chick netrin-1 protein (10 µg/ml), or control affinity purified nonimmune rabbit IgG (10 µg/ml), were added to dorsal thalamic-floor plate and dorsal thalamic-ICZ cocultures. Cocultures were analyzed as described above.
DiI labeling of the TCA projection. Netrin-1
Brains were left in 4% paraformaldehyde at 4°C or 30°C for
3 weeks to allow the DiI to diffuse the full length of the axons. Brains were then embedded in 3% low melting point agar, and 75 or 100 µm coronal sections were cut using a vibratome. Sections were counterstained with a 0.02% solution of the nuclear stain bisbenzimide (Sigma). Labeled cells and axons were photographed under rhodamine (DiI) and UV (bisbenzimide) illumination.
Cortical injection volumes were measured, and pairs of littermates (one wild-type or heterozygote paired with one homozygous mutant) with similarly sized injections (within 10% of each other; as described in Catalano et al., 1998
Distribution of TCAs in the internal capsule. Anterograde DiI labeling and L1 immunostaining were used to examine the distribution of TCAs within the IC. Heads of netrin-1
L1 immunocytochemistry was performed as previously described (Tuttle et al., 1999
RESULTS
Expression of netrin-1 relative to the TCA pathway
Previous studies have reported that netrin-1 is expressed in the striatum of developing rodents (Serafini et al., 1996
As TCAs turn from the diencephalon into the ICZ, they immediately encounter a cluster of netrin-1-expressing cells (Fig. 2A,A'). As TCAs course dorsolaterally and rostrally through the ICZ, their pathway remains in close association with netrin-1-expressing cells (Fig. 2A,A'). Particularly striking is the presence of netrin-1-expressing cells within and in close proximity to fascicles of TCAs passing through the ICZ (Fig. 2A',B). Robust netrin-1 expression is also seen in the lateral and medial ganglionic emminences (Fig. 2B). In addition, netrin-1 is expressed in restricted parts of the diencephalon. Netrin-1 is expressed in medial dorsal thalamus, just lateral to the ventricular zone, and in the hypothalamic ventricular zone (Fig. 2A). At caudal levels, netrin-1 is expressed in the mantle zone of ventral hypothalamus (data not shown). Netrin-1 expression is not detected in the neocortex (Fig. 2A), the target of TCAs. These findings show that netrin-1 is expressed in close association to the path of TCAs as they extend through the ICZ toward the neocortex.
Expression of netrin-1 receptors in dorsal thalamus
The expression pattern of netrin-1 suggests that it may act as an attractant for TCAs. Therefore, we would expect that DCC and neogenin, receptors that mediate the attractant effects of netrin-1 (Keino-Masu et al., 1996
In dorsal thalamus, DCC is expressed in the ventricular zone and in a broad dorsolateral to ventromedial stripe in the mantle zone (Fig. 2C). This stripe includes the VP nucleus, which projects to somatosensory cortex. Expression is also found along the dorsal thalamic-ventral thalamic border, in the region of the zona limitans interthalamica (Fig. 2C). High levels of DCC expression are found elsewhere in the diencephalon, including the habenula and pretectum (Fig. 2C), and in medial ventral thalamus and hypothalamus (data not shown). Neogenin is expressed in a dorsoventral stripe in medial dorsal thalamus, just lateral to the ventricular zone (Fig. 2D), a pattern similar to that of netrin-1 in dorsal thalamus (Fig. 2A). Neogenin expression is also present in the ventral thalamic ventricular zone (data not shown).
In contrast to DCC and neogenin, neither unc5h2 (data not shown) nor unc5h3 (Fig. 2E) are expressed in dorsal thalamus, although both are expressed elsewhere in the diencephalon. Unc5h2 is expressed in anterior parts of ventral thalamus, the ventral thalamic ventricular zone, and the pretectum (data not shown). Unc5h3 expression is present in a region of ventral thalamus that will develop into the ventral lateral geniculate nucleus (Fig. 2E) and in scattered cells in the hypothalamus (data not shown).
These data demonstrate that at the time TCAs are extending through the ICZ, the attractant netrin-1 receptors DCC and neogenin are expressed in dorsal thalamus, but the repellent netrin-1 receptors unc5h2 and unc5h3 are not. Taken together with the expression pattern of netrin-1, these findings suggest that netrin-1 may act to attract TCAs into and/or through the ICZ.
Netrin-1 attracts dorsal thalamic axons in vitro
To test the action of netrin-1 on TCAs, we cocultured at a distance in three dimensional collagen gels (Lumsden and Davies, 1983
Dorsal thalamic explants cultured alone typically exhibit symmetric axon outgrowth (Fig. 3D). In contrast, dorsal thalamic explants cocultured at a distance from floor plate exhibit a statistically significant bias in axon outgrowth toward the floor plate (Fig. 3A,D). To determine whether netrin-1 is responsible for this bias, dorsal thalamic explants were cocultured at a distance from floor plate in the presence of netrin-1 blocking antibodies, or a control IgG. When cocultured in the presence of a control IgG, dorsal thalamic axon outgrowth still shows a statistically significant bias toward the floor plate (Fig. 3B,D). In contrast, when cocultured in the presence of netrin-1 blocking antibodies, the biased growth of dorsal thalamic axons toward floor plate is abolished (Fig. 3C,D). Thus, the floor plate releases a diffusible activity that attracts dorsal thalamic axons in vitro, and this activity is likely to be netrin-1. Dorsal thalamic explants cocultured with aggregates of netrin-1-transfected 293 cells also show biased outgrowth toward the netrin-1 source (Fig. 3E). This biased outgrowth is less robust than that observed in the floor plate cocultures, but is stronger, albeit not statistically significant, than that exhibited by dorsal thalamic explants cocultured with aggregates of parental 293 cells (Fig. 3E). Nonetheless, when taken together, these coculture experiments suggest that netrin-1 acts in vitro as an attractant for dorsal thalamic axons.
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Figure 3. Netrin-1-dependent attraction of dorsal thalamic axons. Explants from the medial half of dorsal thalamus (dTh; see Materials and Methods; E13.5-E14.5 mouse) were cocultured for 1.5-2 d in collagen gels at a distance from floor plate (FP; E17-E18 rat) or aggregates of 293 cells transfected with netrin-1 (dTh-293Net) or the parental plasmid as a control (dTh-293). A, Dorsal thalamic axon outgrowth is biased toward FP. B, Axon outgrowth from dorsal thalamus is also biased toward FP when nonimmune sera (10 µg/ml) is added to the growth medium (GM). C, Axon outgrowth from dorsal thalamus is no longer biased toward FP when netrin-1 blocking antibodies (10 µg/ml) are added to the GM. D, E, Quantification of dorsal thalamic axon responses. N (number of cocultures) values are in parentheses. D, When dorsal thalamus is cultured alone (dTh alone), the distribution of axon outgrowth is significantly different from dorsal thalamus cocultured with FP (GM; p < 0.0002,
TCAs are disorganized and abnormally restricted in the IC of netrin-1
The findings described above suggest that netrin-1 may act in vivo to attract TCAs into the ICZ and direct their growth through it toward the cortex. Therefore, we analyzed the development of the TCA projection in netrin-1
To anterogradely label a substantial proportion of TCAs, large crystals of DiI were placed into dorsal thalamus. At E15.5, TCAs have extended through the IC and entered the neocortex in both wild-type (Fig. 4A-C) and netrin-1
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Figure 4. The path of TCAs is abnormally restricted in E15 netrin-1
To determine whether the restricted distribution of TCAs within the ICZ of netrin-1
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Figure 5. The internal capsule is abnormally narrow, and fascicles of TCAs are disorganized in P0 netrin-1
To control for potential differences in DiI placements, the IC phenotype was verified by immunostaining sections of netrin-1
Together, these data demonstrate that in the absence of netrin-1, TCAs can extend out of dorsal thalamus, through the ventral thalamus and turn as they approach hypothalamus to enter the ICZ in an apparently normal fashion. However, within regions of ICZ that normally would express netrin-1, fascicles of TCAs are disorganized and abnormally restricted to the dorsomedial half of the ICZ/striatum. The path of corticothalamic axons appears to be similarly aberrant. These data suggest that netrin-1 provides a favorable growth substrate for TCAs within the ICZ, and that in the absence of netrin-1, the ICZ is less permissive for TCA growth.
The TCA projection to neocortex is reduced in netrin-1 mutant mice
The finding that the distribution and organization of fascicles of TCAs in the IC is abnormal in netrin-1
A specific population of TCAs were anterogradely labeled by injecting DiI into VP in netrin-1
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Figure 6. The TCA projection is variably reduced in netrin-1
To corroborate the anterograde findings and quantify the reduction in the TCA projection in netrin-1
ICZ releases an attractant activity for dorsal thalamic axons distinct from netrin-1
Previous studies have shown that the ICZ releases an activity that attracts dorsal thalamic axons at a distance in collagen gels (Braisted et al., 1999
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Figure 7. The ICZ releases an attractant activity for dorsal thalamic axons that is distinct from netrin-1. Explants from the medial half of dorsal thalamus (dTh; E13.5-E14.5 mouse) were cocultured for 1.5-2 d in collagen gels at a distance from the location of the ICZ in explants of ventral telencephalon (E13.5-E14.5 mouse). Netrin-1 blocking antibodies (anti-N1; 10 µg/ml) or nonimmune sera (control IgG; 10 µg/ml) were added to the growth medium at the time of plating. The number of cocultures (n) is indicated in parentheses. When cultured in the presence of control IgG, dorsal thalamic axon outgrowth is biased toward the ICZ (A, B). Addition of netrin-1 blocking antibodies diminishes the percentage of dorsal thalamic explants showing biased outgrowth toward the ICZ (B, anti-N1); however, the distributions of dorsal thalamic axon outgrowth in the control IgG and anti-N1 cocultures are not significantly different (p = 0.7,
Netrin-1 enhances dorsal thalamic axon growth in vitro
The restricted distribution of TCAs in the ICZ/striatum and the reduced number of TCAs that reach the cortex suggest that netrin-1 enhances or facilitates TCA growth through this distal portion of their subcortical pathway. Therefore, we tested in vitro whether netrin-1 enhances dorsal thalamic axon outgrowth. Explants of E13.5-E14.5 medial dorsal thalamus were cultured alone in collagen gels with or without soluble recombinant netrin-1 protein added to the growth medium. Dorsal thalamic axon outgrowth observed under control conditions (Fig. 8A) is substantially enhanced in the presence of netrin-1 (Fig. 8B). The addition of netrin-1 results in a statistically significant increase in both the number (Fig. 8C; p < 0.0001) and the length (Fig. 8D; p < 0.01) of dorsal thalamic axon fascicles compared to control conditions. Thus netrin-1 has a significant growth-promoting effect on dorsal thalamic axons in vitro.
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Figure 8. Netrin-1 enhances dorsal thalamic axon outgrowth. Explants from the medial half of dorsal thalamus (dTh) were cultured in collagen gels for 1.5-2 d either in growth medium (A, GM) or in growth medium supplemented with soluble recombinant netrin-1 (B, GM+N1; 400 ng/ml). C, D, Quantification of axon outgrowth at 100 µm (C) and 285 µm (D) from dorsal thalamic explants. The number of cultures analyzed is given in parentheses. A greater number of axons are present at both 100 µm (C) and 285 µm (D) in the cultures to which netrin-1 had been added. The differences in axon outgrowth between the two culture types are significantly different (p < 0.0001 at 100 µm; p < 0.01 at 285 µm, Student's t test). Scale bar, 250 µm.
DISCUSSION
We have used gene expression analyses, in vitro axon guidance assays, and an analysis of the development of the TCA projection in netrin-1
Our in vitro coculture experiments demonstrate that dorsal thalamic axons are attracted at a distance toward floor plate explants. It is likely that netrin-1 is responsible for this attraction because (1) it expressed and released by floor plate (Serafini et al., 1996
Our analyses of netrin-1
An interesting related issue is that even though we find that fascicles of TCAs, and likely corticothalamic axons, are disorganized within the IC, TCAs nonetheless exhibit area-specific targeting. Although our analysis of this issue is limited, these findings suggest that the aberrant deployment of TCAs within the IC, and likely a similar aberrancy in cortical efferent axons (which have been hypothesized to guide TCAs to their correct cortical targets) (Blakemore and Molnar, 1990
Our findings suggest that a major role of netrin-1 in the ICZ is to promote the growth of TCAs through the ventral telencephalon. This interpretation is suggested by both our in vitro finding that soluble netrin-1 applied to the medium enhances axon outgrowth from dorsal thalamic explants, and by our in vivo analyses that reveal a reduction in the TCA projection in netrin-1
Anterograde labeling in netrin-1
The reduction in the TCA projection varies between individual netrin-1
In conclusion, our findings show that netrin-1 expression in the ICZ is required for the proper development of the TCA projection and that in its absence, the TCA projection through the IC is disorganized and abnormally restricted, and a reduced number of TCAs reach cortex. Our findings best support the interpretation that netrin-1 helps delineate the path of TCAs through the ventral telencephalon to the cortex by providing a growth corridor defined here as the ICZ, and that in the absence of netrin-1 the ICZ is less permissive for TCA growth. We cannot rule out though that netrin-1 may also contribute to the turning of TCAs from the diencephalon into the ICZ. In both instances, netrin-1 does not appear to act alone, and likely is one of several attractant molecules expressed in the ICZ that control TCA growth through the ventral telencephalon. In addition to multiple molecular activities in the ICZ, other spatially and functionally distinct cues have been suggested to contribute to TCA pathfinding from dorsal thalamus to the cortex. For example, the hypothalamus releases a repellent activity for TCAs that has been suggested to promote their turning into the ICZ (Braisted et al., 1999
FOOTNOTES Received Dec. 17, 1999; revised May 11, 2000; accepted May 12, 2000.
This work was supported by National Institutes of Health Grants R01 NS31558 (D.D.M.O'L.) and R01 EY02858 (C.J.S.), and fellowship National Research Service Award EY06491 (S.M.C.). C.J.S. and M.T.L. are Investigators of the Howard Hughes Medical Institute.
Correspondence should be addressed to Dennis D. M. O'Leary, MNL-O, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037. E-mail: doleary{at}salk.edu.
Dr. Kennedy's present address: Montreal Neurological Institute, Montreal, Quebec Canada H3A 2B4.
Dr. Catalano's present address: Roche Bioscience, R2-101, 3401 Hillview Avenue, Palo Alto, CA 94304.
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