|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
1 Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037 USA
2 Department of Neurosciences, University of California San Diego, La Jolla, CA 92093 USA
Present address: Telethon Foundation at CNR Istituto Tecnologie Biomediche, 20090 Segrate (Milan), Italy
*Author for correspondence (e-mail: lemke{at}salk.edu)
Accepted 6 November 2001
 |
SUMMARY |
|---|
 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Key words: Retina, Homeobox, Vax genes, Emx genes, Dorsoventral axis, Axon guidance, Mouse
|
INTRODUCTION |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). These receptors and ligands act in concert to organize retinocollicular connections into a topographic map – a spatial ordering of axonal connections in which the Cartesian coordinates of a two-dimensional sheet of projecting RGC neurons are mapped onto the coordinates of a second two-dimensional sheet of target neurons in the SC. In the retinocollicular map, axons from RGCs in the nasal retina project to and form synapses in the caudal end of the SC, while RGCs in the temporal retina project to targets in the rostral SC. RGCs located at intermediate NT retinal positions project to correspondingly intermediate caudal-rostral positions in the SC. The dorsoventral (DV) axis of the retina is similarly mapped onto the lateral-medial axis of the SC.
The proteins most closely tied to the topography of retinocollicular mapping are the receptor tyrosine kinases of the EphA family, together with their ligands, the ephrin-A proteins (Flanagan and Vanderhaeghen, 1998; O’Leary and Wilkinson, 1999). Two key lines of recent genetic evidence (Frisén et al., 1998; Brown et al., 2000; Feldheim et al., 2000), together with a large body of earlier in vitro membrane stripe and in vivo misexpression studies, have demonstrated that a low-nasal-to-high-temporal retinal EphA receptor gradient, combined with a reciprocal low-rostral-to-high-caudal collicular ephrin-A gradient, serve to order the mapping of the NT axis of the retina onto the caudal-rostral axis of the SC. The cell-surface molecules that mediate mapping of the orthogonal retinocollicular axes are less well understood. Although clear DV gradients of EphB2 and EphB3 receptor expression have been observed in the vertebrate retina, and medial-lateral gradients of ephrin-B ligands have been detected in the SC (Marcus et al., 1996; Braisted et al., 1997; Holash et al., 1997; Schulte et al., 1999), these gradients are not reciprocally configured, as would be required for a chemorepellent action of the ephrin-Bs, and genetic tests of the importance of the EphB/ephrin-B signaling system to retinocollicular mapping have yet to be reported.
Less clear still are the transcriptional control mechanisms through which the NT and DV retinal gradients of the EphA and EphB receptors are established during development. Recently, two candidates for transcriptional regulators of DV polarization of the retina – Tbx5 and Vax2 – have been identified (Barbieri et al., 1999; Koshiba-Takeuchi et al., 2000; Schulte et al., 1999). Vax2 (for ventral anterior homeobox 2) is one of two vertebrate-specific homeobox genes that are structurally related to, and that have almost certainly evolved from the duplication of, the vertebrate Emx genes (Barbieri et al., 1999; Hallonet et al., 1998; Ohsaki et al., 1999). Loss-of-function experiments for Vax1 have demonstrated that its product plays essential roles in axon guidance and major tract formation in the developing forebrain (Bertuzzi et al., 1999; Hallonet et al., 1999). Vax2, which carries a homeodomain identical to that of Vax1, is a candidate regulator of the retinal DV axis for two reasons. First, it is steeply graded in its expression along this axis in chick and frog embryos, with highest expression ventrally. And second, dominant gain-of-function studies in these embryos have shown that, when misexpressed in the dorsal retina, Vax2 is capable of ventralizing this tissue, as assessed by (1) the altered expression of DV marker genes, both putative guidance cues such as EphB2/B3 and putative transcriptional regulators such as Tbx5, and (2) the altered projection of RGC axons to the midbrain. These observations have been interpreted as indicating that Vax2 may function as a global ‘ventralizing’ regulator of the developing eye. In this report, we describe the generation of Vax2–/– mice, and the use of these mutants to perform loss-of-function tests of this hypothesis.
|
MATERIALS AND METHODS |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). Electroporated W95 embryonic stem (ES) cell clones were doubly selected with G418 and FIAU, and were screened for homologous recombination by Southern blot, using the 230 bp 3'-external probe indicated in Fig. 1. Four positive ES cell clones were microinjected into C57/Bl6 blastocysts to generate chimeric mice, which were then mated with C57/Bl6 to produce heterozygous knockouts, all according to standard procedures (Capecchi, 1989). Although most Vax2–/– mice did not exhibit overt postnatal phenotypes, 
7% of homozygotes were abnormal, in that they either were unusually small in size, exhibited a trembling phenotype or displayed small eyes.
|
; Zhadanov et al., 1995). Dissected mouse embryos were anesthetized and immersion fixed in 4% paraformaldehyde/PBS overnight at 4°C, followed by overnight infiltration with 20% sucrose. Cryoprotected tissues were then embedded in OCT medium (Miles). Hybridization was performed with 20 µm coronal and transverse sections of retina at birth (P0), and with embryos at E9.5, E11.5 and E14.
Axon tracing
In vivo anterograde labeling was performed between postnatal day 7 (P7) and P9 by focal injection of 1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (DiI) (Molecular Probes; 8% w/v in N,N-dimethylformamide) into the left eye, as described previously (Brown et al., 2000; Simon and O’Leary, 1992). Mice were sacrificed 1 day later, and termination zone (TZ) number and location in the contralateral superior colliculi were analyzed using a Zeiss LSM510 confocal microscope. The size and location of focal retinal DiI injection sites were identified post hoc.
Intraocular injection of fluorescently tagged cholera toxin B-subunit tracers (CTB) into one eye allowed for visualization of both ipsilateral and contralateral retinal projections. For anterograde tracing of the RGC axons, CTB conjugated to a fluorescein (FITC) fluorophore (List Biological Laboratories, Campbell, CA) was made in a 0.2% solution in 1% DMSO. Whole eye fill injections were carried out at P8 and the animals were perfused with 4% paraformaldehyde 24 hours later. Brains were cut coronally in 200 µm sections and subsequent imaging was performed using a confocal microscope (Zeiss).
|
RESULTS |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
; Schulte et al., 1999), the two Vax genes nonetheless exhibit distinct and largely complementary patterns of expression during embryogenesis in the mouse. At embryonic day 10.5 (E10.5) and thereafter, Vax1 mRNA is expressed in the ventral diencephalon and telencephalon, and in the optic stalk and disk, but is not prominently expressed in the developing neural retina (Bertuzzi et al., 1999; Hallonet et al., 1999). By contrast, the expression of mouse Vax2 mRNA is largely confined to the ventral half of the developing eye itself (Fig. 1A). These distinct embryonic expression domains in the mouse contrast with the situation in the chick, where a single gene (VAX) exhibits a hybrid Vax1/Vax2-like expression profile throughout the ventral diencephalon, optic stalk, and ventral retina (Schulte et al., 1999). At E11.5, mouse Vax2 mRNA is expressed in all cells of the ventral neural retina (Fig. 1B), but by birth becomes restricted to ventral RGCs (Fig. 1E). In addition to the previously reported high-ventral-to-low-dorsal retinal gradient of Vax2 mRNA (Fig. 1B,E), we have observed a shallower Vax2 gradient along the NT axis, with highest expression nasally (Fig. 1B-D,F). This dually polarized expression is evident throughout the neural retina at E14 (Fig. 1C,D), when RGC axons first reach the SC, and persists at least until birth in the mouse, when the DV patterning of RGC projections is well under way. The double Vax2 retinal gradient in the mouse is similar in orientation and configuration to the recently described dual retinal expression gradient of the bone morphogenetic protein 4 (BMP4) antagonist ventroptin in the chick (Sakuta et al., 2001).
Inactivation of the mouse Vax2 gene
In order to test the hypothesis that Vax2 may specify positional identity in the retina along the DV axis (Barbieri et al., 1999; Schulte et al., 1999), we generated Vax2 mutant mice (Fig. 1G-I). We replaced exon 2 of the mouse Vax2 gene, which encodes the first two essential 
helices of the Vax2 homeodomain, with a G418 resistance (PGK-neo) cassette. In addition to deleting exon 2, this mutation introduces a frame shift that eliminates all Vax2-coding sequence downstream of exon 2 (see Fig. 1G, Materials and Methods).
Retinocollicular mapping in the Vax2 mutants
We first analyzed the projection of RGC axons from the retina to the SC in the Vax2 mutants. Normally, the DV and NT axes of the retina are precisely mapped onto the correspondingly orthogonal lateral-medial and caudal-rostral axes of the SC (Brown et al., 2000). If Vax2 is required for ventral patterning of the retina, then ventral RGCs that lack Vax2 should be dorsalized in terms of their projection to the SC; that is, they should project to lateral rather than to medial SC. In mice, the topography of the retinocollicular map is mature by postnatal day 7 (P7) (O’Leary et al., 1986). We found that most of the Vax2–/– mice (94 out of 101) were healthy and superficially normal for many months after birth; in marked contrast to Vax1 mutants (Bertuzzi et al., 1999), no postnatal colobomata were observed. We therefore labeled discrete loci of RGCs and their projecting axons across the full extent of the NT and DV axes of the mutant retina at P7-9. We performed focal injections of the lipophilic axon tracer DiI (Fig. 2), and then analyzed labeled projections to the contralateral SC 1 day later (see Materials and Methods). In total, we analyzed 40 injections (from 40 mutant mice). The Vax2 mutant retinae that we selected for study were histologically indistinguishable from wild type in terms of retinal lamination, cellular density, organization of plexiform layers and closure of the optic disk (data not shown).
|
Unexpectedly, however, the dorsalization of RGC projections became progressively less severe as DiI injections were moved to increasingly nasal regions of the ventral retina. At 80-85% of the retinal NT axis (where extreme temporal=100%), ventral RGC TZs remained aberrantly lateralized in their SC projection, but more than one lateral TZ was typically observed (Fig. 2G,H). As injections were moved to 60-80% of the NT axis, the size of ectopic lateralized TZs became progressively smaller, and an appropriate TZ appeared very near the expected medial position (Fig. 2I-K). For mid-ventral injections into the Vax2 mutant retinae (30-60% of the NT axis), collicular TZs typically appeared near the expected medial location, occasionally as single, well-formed TZs (Fig. 2M). When ectopic lateral TZs were observed, they were most frequently small (Fig. 2B, lower panel and Fig. 2N-R). Finally, ventral DiI injections into the most nasal regions of the Vax2 mutant retina (0-30% of the retinal NT axis) almost always yielded single tight TZs at the expected wild-type location in the medial SC (Fig. 2C, Fig. 2T-W). Innervation space in the rostral medial quadrant of the Vax2–/– SC vacated by lateralized ventral temporal RGC axons appeared to be occupied by TZs from RGCs whose axons would normally occupy extreme medial locations near the midpoint of the RC axis (Fig. 2L). Thus, the Vax2–/– axon projection phenotype progressed from extremely strong and fully penetrant in the ventral temporal retina (Fig. 2A,D-F) to almost non-existent in the ventral nasal retina (Fig. 2C,U-W). Note that this NT phenotypic progression is the inverse of the shallow gradient of Vax2 mRNA (see Discussion).
Maintenance of ipsilateral projections
At maturity, the vast majority (>95%) of RGC axons in the mouse cross at the optic chiasm and innervate the contralateral SC; the rare ipsilateral projections originate primarily in the ventral temporal quadrant of the retina (Sretavan and Kruger, 1998). Although ventral temporal RGC projections are those that are most strongly perturbed in the contralateral SCs of the Vax2 mutants, we nonetheless consistently detected ipsilateral RGC projections after full eye fills with fluorescent anterograde axonal tracers in these mice (Fig. 3; n=5). Indeed, in some mice, these ipsilateral projections appeared to be atypically abundant.
|
; Schulte et al., 1999). Similarly, mRNA encoding a dorsally restricted transcription factor and presumed DV regulator – Tbx5 – is downregulated by these gain-of-function manipulations. Consistent with a subset of these earlier observations, we found that ventral expression of both the Ephb2 and Ephb3 mRNAs was lost in the Vax2–/– ventral retina (Fig. 4A and data not shown), and that conversely, ventral expression of the ephrin-B1 and ephrin-B2 mRNAs (Efnb1 and Efnb2 – Mouse Genome Informatics) was acquired (Fig. 4B and data not shown). In addition to these DV alterations, and consistent with our detection of a shallow NT Vax2 gradient, we also observed a partial reordering of the retinal NT axis in the ventral retina of the Vax2–/– mutants. For example, Epha5 mRNA, which is normally distributed in a low-nasal-to-high-temporal gradient throughout the DV axis (Brown et al., 2000), was upregulated in the ventral nasal mutant retina (Fig. 4C). Thus, each of the above changes leads to flattened or abolished gradients of guidance cue mRNAs that are normally graded along both the DV and NT axes (compare left and right panels in Fig. 4A-C). This global regulation of multiple guidance cues is apparently crucial, as preliminary analysis of mice doubly mutant for the Ephb2 and Ephb3 genes indicates that medial-lateral RGC axon targeting defects in these double EphB mutants are much less pronounced than those detailed above for the Vax2 single mutants (R. H., T. McLaughlin and D. D. M. O., unpublished).
|
; Schulte et al., 1999) remained graded, low-dorsal-to-high-ventral, in early Vax2 mutant embryos (data not shown). Similarly, the inverse high-dorsal-to-low-ventral gradient of mRNA encoding the T box transcription factor Tbx5, which is the earliest known dorsal retinal marker (Koshiba-Takeuchi et al., 2000), was, unlike ephrin-B1 and -B2, unchanged in the Vax2 mutants at E10.5 and P0 (Fig. 4D, and data not shown). Although gain-of-function Vax2 misexpression experiments have suggested that Tbx5 is normally repressed by Vax2 (Schulte et al., 1999), our results demonstrate that this is not the case: loss of Vax2 in the ventral retina does not lead to Tbx5 upregulation. As Tbx5 misexpression experiments have similarly suggested that Vax2 may be repressed by Tbx5 (Koshiba-Takeuchi et al., 2000), analysis of retinal polarity in Tbx5 loss-of-function mutants will be required in order to clarify the relationship between these transcription factors. Nonetheless, our results indicate that the highly polarized expression of Tbx5 does not require Vax2. Similarly, the homeodomain protein Six6 and the winged-helix transcription factor Bf1 (Foxg1 – Mouse Genome Informatics) (Huh et al., 1999; Lopez-Rios et al., 1999), which are also hypothesized regulators of retinal axial polarity, and which at E9.5 exhibit expression in the ventral nasal (Bf1) and ventral temporal (Six6) mouse retina, respectively (Fig. 4E,F), were unchanged in their expression domains in the Vax2 mutants (Fig. 4G, and data not shown). These domains are dynamic for both Bf1 and Six6 from E9.5 to birth: Bf1 is first expressed in the ventral nasal retina (Fig. 4E) and by E12.5 moves to the dorsal nasal retina; and Six6 is first detected in the ventral temporal retina (Fig. 4F), but later occupies the entirety of the retina. These dynamic expression domains were unaffected in the Vax2 mutants, as assessed by in situ hybridization at E10.5, E12.5, E14.5, E16.5 and P0 (Fig. 4G, and data not shown). |
DISCUSSION |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
These results notwithstanding, our analyses also demonstrate that the ventralizing influence of Vax2 is in two respects incomplete. First, although Vax2 expression normally extends across the entirety of the ventral retina, the dorsalization of RGC projections in the Vax2 mutant retina does not. As detailed above (Fig. 2), dorsalization is robust only in the extreme ventral temporal retina, and becomes progressively less severe in progressively more nasal regions of the retina. In the extreme ventral nasal retina, mutant RGC projections are indistinguishable from wild type. And second, some of the phenotypes seen upon loss of Vax2 are not consistent with those reported for Vax2 gain-of-function studies. Most notably, loss of Vax2 does not lead to the activation of Tbx5 expression in the ventral retina, or to any other obvious perturbation in the high-dorsal-to-low-ventral gradient of Tbx5 expression. These latter observations suggest that transcriptional specifiers of vertebrate retinal polarity, like many transcriptional specifiers of retinal identity (Marquardt et al., 2001), operate independently.
The surprising finding that the axonal targeting errors of ventral temporal RGCs are much more severe than those of ventral nasal RGCs suggests that either: (1) Vax2 interacts with one or more additional transcriptional regulators that are similarly graded along the DV and NT axes, such that a ‘limiting concentration effect’ of these nuclear proteins is detected in the mutants only in the retinal quadrant where their aggregate level is normally lowest (Fig. 5A); or (2) the Vax2 gene, which is steeply graded along the retinal DV axis, normally interacts genetically with one or more genes that are steeply graded along the NT axis (Fig. 5B). With regard to the second possibility, other homeodomain transcription factor genes, such as SOHO1 and GH6 in the chick (Schulte and Cepko, 2000), have been shown to be graded along the retinal NT axis, and have been hypothesized to control the expression of NT guidance cues such as EphA receptors and their ephrin-A ligands. The homologs of SOHO1 and GH6 remain to be analyzed in the mouse, but the transcription factor Bf1 is specifically expressed, from E8.5-E9.5, in the mouse ventral nasal retina (Fig. 4E). Although the EphA/ephrin-A guidance cues have been analyzed almost exclusively in terms of RGC mapping along the rostral-caudal axis of the SC (Brown et al., 2000; Feldheim et al., 2000), it is interesting to note that medial-lateral mapping anomalies have been consistently observed in ephrin-A2/A5 double mutants (Feldheim et al., 2000). If, as schematized in Fig. 5B, Vax2 normally acts in concert with one or more transcription factors that are graded along the NT axis, then RGCs in the ventral temporal retina would again be those most sensitive to the loss of Vax2. Direct tests of these and related models must await the generation and analysis of a set of single and compound mutants of Vax2 with Bf1, SOHO1, GH6, ephrin-A2 and ephrin-A5, among others.
|
|
ACKNOWLEDGMENTS |
|---|
|
REFERENCES |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Barbieri, A., Lupo, G., Bulfone, A., Andreazzoli, M., Mariani, M., Fougerousse, F., Consalez, G., Borsani, G., Beckmann, J., Barsacchi, G. et al. (1999). A homeobox gene, Vax2, controls the patterning of the eye dorsoventral axis. Proc. Natl. Acad. Sci. USA 96, 10729-10734.
Bertuzzi, S., Hindges, R., Mui, S., O’Leary, D. and Lemke, G. (1999). The homeodomain protein Vax1 is required for axon guidance and major tract formation in the developing forebrain. Genes Dev. 13, 3092-3105.
Braisted, J., McLaughlin, T., Wang, H., Friedman, G., Anderson, D. and O’Leary, D. (1997). Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system. Dev. Biol. 191, 14-28.[Medline]
Brown, A., Yates, P., Burrola, P., Ortuno, D., Vaidya, A., Jessell, T., Pfaff, S., O’Leary, D. and Lemke, G. (2000). Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102, 77-88.[Medline]
Capecchi, M. (1989). Altering the genome by homologous recombination. Science 244, 1288-1292.
Feldheim, D., Kim, Y., Bergemann, A., Frisen, J., Barbacid, M. and Flanagan, J. (2000). Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563-574.[Medline]
Flanagan, J. and Vanderhaeghen, P. (1998). The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309-345.[Medline]
Frisén, J., Yates, P., McLaughlin, T., Friedman, G., O’Leary, D. and Barbacid, M. (1998). Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20, 235-243.[Medline]
Hallonet, M., Hollemann, T., Wehr, R., Jenkins, N., Copeland, N., Pieler, T. and Gruss, P. (1998). Vax1 is a novel homeobox-containing gene expressed in the developing anterior ventral forebrain. Development 125, 2599-2610.[Abstract]
Hallonet, M., Hollemann, T., Pieler, T. and Gruss, P. (1999). Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system. Genes Dev. 13, 3106-3114.
Holash, J., Soans, C., Chong, L., Shao, H., Dixit, V. and Pasquale, E. (1997). Reciprocal expression of the Eph receptor Cek5 and its ligand(s) in the early retina. Dev. Biol. 182, 256-269.[Medline]
Huh, S., Hatini, V., Marcus, R., Li, S. and Lai, E. (1999). Dorsal-ventral patterning defects in the eye of BF-1-deficient mice associated with a restricted loss of shh expression. Dev. Biol. 211, 53-63.[Medline]
Koshiba-Takeuchi, K., Takeuchi, J., Matsumoto, K., Momose, T., Uno, K., Hoepker, V., Ogura, K., Takahashi, N., Nakamura, H., Yasuda, K. et al. (2000). Tbx5 and the retinotectum projection. Science 287, 134-137.
Lopez-Rios, J., Gallardo, M., de Cordoba, S. and Bovolenta, P. (1999). Six9(Optx2), a new member of the Six gene family of transcription factors, is expressed at early stages of vertebrate ocular and pituitary development. Mech. Dev. 83, 155-159.[Medline]
Marcus, R. C., Gale, N. W., Morrison, M. E., Mason, C. A. and Yancopoulos, G. D. (1996). Eph family receptors and their ligands distribute in opposing gradients in the developing mouse retina. Dev. Biol. 180, 786-789.[Medline]
Marquardt, T., Ashery-Padan, R., Andrejewski, N., Scardigli, R., Guillemot, F. and Gruss, P. (2001). Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105, 43-55.[Medline]
O’Leary, D., Fawcett, J. and Cowan, W. (1986). Topographic targeting errors in the retinocollicular projection and their elimination by selective ganglion cell death. J. Neurosci. 6, 3692-3705.[Abstract]
O’Leary, D. and Wilkinson, D. (1999). Eph receptors and ephrins in neural development. Curr. Opin. Neurobiol. 9, 65-73.[Medline]
O’Leary, D., Yates, P. and McLaughlin, T. (1999). Molecular development of sensory maps: representing sights and smells in the brain. Cell 96, 255-269.[Medline]
Ohsaki, K., Morimitsu, T., Ishida, Y., Kominami, R. and Takahashi, N. (1999). Expression of the Vax family homeobox genes suggests multiple roles in eye development. Genes Cells 4, 267-276.[Abstract]
Sakuta, H., Suzuki, R., Takahashi, H., Kato, A., Shintani, T., Iemura, S., Yamamoto, T., Ueno, N. and Noda, M. (2001). Ventroptin: A BMP-4 antagonist expressed in a double-gradient pattern in the retina. Science 293, 111-115.
Schulte, D. and Cepko, C. (2000). Two homeobox genes define the domain of EphA3 expression in the developing chick retina. Development 127, 5033-5045.[Abstract]
Schulte, D., Furukawa, T., Peters, M., Kozak, C. and Cepko, C. (1999). Misexpression of the Emx-related homeobox genes cVax and mVax2 ventralizes the retina and perturbs the retinotectal map. Neuron 24, 541-553.[Medline]
Simon, D. and O’Leary, D. (1992). Development of topographic order in the mammalian retinocollicular projection. J. Neurosci. 12, 1212-1232.[Abstract]
Sretavan, D. and Kruger, K. (1998). Randomized retinal ganglion cell axon routing at the optic chiasm of GAP-43-deficient mice: association with midline recrossing and lack of normal ipsilateral axon turning. J. Neurosci. 18, 10502-10513.
Tybulewicz, V., Crawford, C., Jackson, P., Bronson, R. and Mulligan, R. (1991). Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153-1163.[Medline]
Zhadanov, A., Bertuzzi, S., Taira, M., Dawid, I. and Westphal, H. (1995). Expression pattern of the murne LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues. Dev. Dyn. 202, 354-364.[Medline]
This article has been cited by other articles:
|
|
 |
|
  D. T. Plas, O. S. Dhande, J. E. Lopez, D. Murali, C. Thaller, M. Henkemeyer, Y. Furuta, P. Overbeek, and M. C. Crair Bone Morphogenetic Proteins, Eye Patterning, and Retinocollicular Map Formation in the Mouse J. Neurosci., July 9, 2008; 28(28): 7057 - 7067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Garcia-Frigola, M. I. Carreres, C. Vegar, C. Mason, and E. Herrera Zic2 promotes axonal divergence at the optic chiasm midline by EphB1-dependent and -independent mechanisms Development, May 15, 2008; 135(10): 1833 - 1841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Harada, C. Harada, and L. F. Parada Molecular regulation of visual system development: more than meets the eye Genes & Dev., February 15, 2007; 21(4): 367 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Butler and G. Tear Getting axons onto the right path: the role of transcription factors in axon guidance Development, February 1, 2007; 134(3): 439 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sakuta, H. Takahashi, T. Shintani, K. Etani, A. Aoshima, and M. Noda Role of bone morphogenic protein 2 in retinal patterning and retinotectal projection. J. Neurosci., October 18, 2006; 26(42): 10868 - 10878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Kim and G. Lemke Hedgehog-regulated localization of Vax2 controls eye development. Genes & Dev., October 15, 2006; 20(20): 2833 - 2847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Ma Transcriptional regulation of neuronal phenotype in mammals J. Physiol., September 1, 2006; 575(2): 379 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Morcillo, J. R. Martinez-Morales, F. Trousse, Y. Fermin, J. C. Sowden, and P. Bovolenta Proper patterning of the optic fissure requires the sequential activity of BMP7 and SHH Development, August 15, 2006; 133(16): 3179 - 3190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Molotkov, N. Molotkova, and G. Duester Retinoic acid guides eye morphogenetic movements via paracrine signaling but is unnecessary for retinal dorsoventral patterning Development, May 15, 2006; 133(10): 1901 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sen, S. Harpavat, M. A. Peters, and C. L. Cepko Retinoic acid regulates the expression of dorsoventral topographic guidance molecules in the chick retina Development, December 1, 2005; 132(23): 5147 - 5159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Picker and M. Brand Fgf signals from a novel signaling center determine axial patterning of the prospective neural retina Development, November 15, 2005; 132(22): 4951 - 4962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Mui, J. W. Kim, G. Lemke, and S. Bertuzzi Vax genes ventralize the embryonic eye Genes & Dev., May 15, 2005; 19(10): 1249 - 1259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Alfano, C. Vitiello, C. Caccioppoli, T. Caramico, A. Carola, M. J. Szego, R. R. McInnes, A. Auricchio, and S. Banfi Natural antisense transcripts associated with genes involved in eye development Hum. Mol. Genet., April 1, 2005; 14(7): 913 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lupo, Y. Liu, R. Qiu, R. A. S. Chandraratna, G. Barsacchi, R.-Q. He, and W. A. Harris Dorsoventral patterning of the Xenopus eye: a collaboration of Retinoid, Hedgehog and FGF receptor signaling Development, April 1, 2005; 132(7): 1737 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Schulte, M. A. Peters, J. Sen, and C. L. Cepko The Rod Photoreceptor Pattern Is Set at the Optic Vesicle Stage and Requires Spatially Restricted cVax Expression J. Neurosci., March 16, 2005; 25(11): 2823 - 2831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Murali, S. Yoshikawa, R. R. Corrigan, D. J. Plas, M. C. Crair, G. Oliver, K. M. Lyons, Y. Mishina, and Y. Furuta Distinct developmental programs require different levels of Bmp signaling during mouse retinal development Development, March 1, 2005; 132(5): 913 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Leconte, L. Lecoin, P. Martin, and S. Saule Pax6 Interacts with cVax and Tbx5 to Establish the Dorsoventral Boundary of the Developing Eye J. Biol. Chem., November 5, 2004; 279(45): 47272 - 47277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Taglialatela, J. M. Soria, V. Caironi, A. Moiana, and S. Bertuzzi Compromised generation of GABAergic interneurons in the brains of Vax1-/- mice Development, September 1, 2004; 131(17): 4239 - 4249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Pratt, N. M. M.-L. Tian, T. I. Simpson, J. O. Mason, and D. J. Price The winged helix transcription factor Foxg1 facilitates retinal ganglion cell axon crossing of the ventral midline in the mouse Development, August 1, 2004; 131(15): 3773 - 3784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhang, Z. Jin, and Z.-Z. Bao Disruption of gradient expression of Zic3 resulted in abnormal intra-retinal axon projection Development, April 1, 2004; 131(7): 1553 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Murai and E. B. Pasquale `Eph'ective signaling: forward, reverse and crosstalk J. Cell Sci., July 15, 2003; 116(14): 2823 - 2832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. McLaughlin, R. Hindges, P. A. Yates, and D. D. M. O'Leary Bifunctional action of ephrin-B1 as a repellent and attractant to control bidirectional branch extension in dorsal-ventral retinotopic mapping Development, June 1, 2003; 130(11): 2407 - 2418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
