Ipsilateral Optic Tract Research Articles

BMP Signaling Interferes with Optic Chiasm Formation and Retinal Ganglion Cell Pathfinding in Zebrafish.

Decussation of axonal tracts is an important hallmark of vertebrate neuroanatomy resulting in one brain hemisphere controlling the contralateral side of the body and also computing the sensory information originating from that respective side. Here, we show that BMP interferes with optic chiasm formation and RGC pathfinding in zebrafish. Experimental induction of BMP4 at 15 hpf results in a complete ipsilateral projection of RGC axons and failure of commissural connections of the forebrain, in part as the result of an interaction with shh signaling, transcriptional regulation of midline guidance cues and an affected optic stalk morphogenesis. Experimental induction of BMP4 at 24 hpf, resulting in only a mild repression of forebrain shh ligand expression but in a broad expression of pax2a in the diencephalon, does not per se prevent RGC axons from crossing the midline. It nevertheless shows severe pathologies of RGC projections e.g., the fasciculation of RGC axons with the ipsilateral optic tract resulting in the innervation of one tectum by two eyes or the projection of RGC axons in the direction of the contralateral eye.

Assessment of optic nerve and optic tract alterations in patients with orbital space-occupying lesions using probabilistic diffusion tractography.

To investigate the diffusion changes in both the optic nerve and optic tract in orbital space-occupying lesion patients with decreased visual acuity, and its clinical significance using probabilistic diffusion tractography (PDT). Twenty patients with orbital space-occupying lesions and 25 age- and gender-matched healthy persons were included. All patients and controls underwent routine orbital magnetic resonance imaging and diffusion tensor imaging (DTI), using a 3.0T magnetic resonance scanner (Trio Tim Siemens). After the image data were preprocessed, each DTI parameters of the optic nerve and optic tract was obtained by PDT, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). The asymmetry index (AI) of each parameter was calculated. Compared the parameters of the affected side optic nerve and ipsilateral optic tract with the contralateral side by paired sample t-test; compared AI of parameters of optic nerve and optic tract between the patient group and the control group by independent sample t-test. Patients were divided into three subgroups according to the low vision grade standard of WHO, compared the FA and AI of FA between the three subgroups by single factor variance analysis. The affected side optic nerve presented significantly decreased FA, increased MD, AD, and RD values compared to the unaffected side (P<0.05). The AI of FA, MD, AD, and RD of optic nerve in the patients was significantly higher than that of the controls (P<0.05). The comparison results of the optic tract showed that there was no significant difference between the patient group and control group in terms of the bilateral optic tracts in patients (P>0.05). The AIs of the FA value of the optic nerve in the eyesight <0.1 subgroup was significantly higher than that in the other groups (P<0.05). FA, MD, AD, and RD of the affected side optic nerve of the orbital space-occupying lesions have significantly changed, the FA value is the most sensitive. The PDT could be a useful tool to provide valid quantitative markers of optic nerve injuries and evaluate the severity of orbital diseases, which other examinations cannot be acquired.

Contralateral Minimum Anterior and Posterior Combined Petrosal Approach for Retrochiasmatic Craniopharyngiomas: An Alternative Technique.

Retrochiasmatic craniopharyngiomas (RC) are a challenge for the neurosurgeon to treat surgically, restrained by their location in the interpeduncular fossa, surrounded by vital neurovascular structures, narrow corridor and poor visibility. Many approaches are possible and elucidated in the literature, which the surgeon chooses, based on multiple factors, such as the size of tumor, calcification, laterality, preoperative neurological deficits and the endocrine function status, recurrence, postradiotherapy status, or significant superior and/or posterior extension. 1 2 We describe a contralateral minimum anterior and posterior (CL-MAPC) petrosal approach for a case of recurrent RC, in a 37-year-old female patient operated before using a pterional approach, now presented with left homonymous hemianopia and panhypopituitarism ( Fig. 1 ). We preferred a contralateral approach to protect the ipsilateral optic tract (OT) from retraction injury, which formed an obstacle to the tumor from ipsilateral side. Apart from various benefits described by the author previously for RC, using MAPC petrosal approach, the CL-MAPC offers a safe corridor, protecting the ipsilateral OT, visualization of tumor origin usually posterior to chiasm, wider corridor if PCoM could be sacrificed, as it was done in this case, and pituitary stalk identification, with a probability of its functional preservation, unlike a necessity of pituitary transposition in EEA, though the endocrine outcome is poor after a radical resection irrespective of the approach chosen. 1 3 4 There was complete excision of the tumor with preservation of visual function postoperatively. We recommend the use of CL-MAPC as an alternative to EEA in some specific indications when the tumor is large, calcified, obscuring OT on the ipsilateral side and with significant lateral extension, which may be limiting factors in EEA ( Fig. 2 ). The link to the video can be found at: https://youtu.be/gWCJmh4_evs .

Evaluation of changes in magnetic resonance diffusion tensor imaging of the bilateral optic tract in monocular blind rats

Some studies have used diffusion tensor imaging (DTI) to investigate white matter development of the visual pathway in humans and animals after visual deprivation. However, the alterations in the bilateral optic tract after the transection of unilateral optic nerve have not been well explored. In this study, we attempted to investigate the structural integrity of and pathological changes to the bilateral optic tract after transection of the unilateral optic nerve in rats using DTI. Eight healthy male Sprague-Dawley (SD) rats were randomly divided into 2 groups, with 4 in each group. Group A served as a control group. Transection of the unilateral (right) optic nerve was performed in the four rats in group B at seven days after birth to establish the early monocular blind model. Four months after the operation, MnCl2 was injected into the left eyes of all rats, and MRI examinations were performed 24h after injection. We detect the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values of the bilateral optic tract in all rats. In a comparison of the ipsilateral optic tract of group B with group A, a significant decrease in FA (P<0.001) and an increase in RD (P<0.01) of the left optic tract were found in group B, while no significant difference was found in the right optic tract. In group B, the FA and RD values of the left optic tract were significantly lower (P<0.01) and significantly higher (P<0.05), respectively, than those of the right optic tract. Consequently, transection of the right optic nerve can lead to structural integrity damage of and pathological changes to the left optic tract in rats. Some DTI-derived parameters (such as FA and RD) may serve as biomarkers of optic tract degeneration.

Application of diffusion tensor imaging in tracking visual pathway fiber bundles in postoperative intensity-modulated radiotherapy for cerebral gliomas

Objective To analyze the feasibility of incorporation of tracking visual pathway fiber bundles by diffusion tensor imaging (DTI) in computed tomography (CT) simulation to develop a protective radiotherapy regimen for cerebral gliomas. Methods A total of 31 patients with cerebral gliomas who were admitted to our hospital from 2013 to 2015 and planed to receive postoperative radiotherapy were enrolled as subjects. All patients underwent CT simulation, conventional or contrast-enhanced magnetic resonance imaging, and DTI. The obtained DTI images of visual pathway fiber bundles were fused with 3DT1 anatomical scans and then imported into the treatment planning system. A protective treatment plan (setting the entire visual pathway fiber bundles as organs at risk (OARs)) and a conventional treatment plan were made for intensity-modulated radiotherapy (IMRT). Comparison of treatment outcomes was made by paired t test. Results There were no significant differences in the conformity index and heterogeneity index of the planning target volume between the two treatment plans (P=0.875, 0.597), both of which had sufficient radiation doses to the target volume and conventional OARs protected. For the patients undergoing the protective treatment plan, the Dmax and Dmean values were reduced to 9.01% and 9.05%, respectively, in the ipsilateral optic tract and to 17.96% and 15.52%, respectively, in the contralateral optic tract; the Dmax and Dmean values were reduced to 5.37% and 5.48%(P=0.000), respectively, in the ipsilateral optic radiation tract and to 12.89% and 11.21%(P=0.000), respectively, in the contralateral optic radiation tract. Conclusions The protective treatment plan based on CT simulation combined with the display of visual pathway fiber bundles by DTI can reduce the radiation dose to the entire visual pathway fiber bundles, which keeps the risk of visual dysfunction after radiotherapy as low as possible. Key words: Diffusion tensor imaging; Visual pathway fiber bundle; Cerebral gliomas; Intensity modulated radiotherapy; Organs at risk

Three-dimensional evaluation of retinal ganglion cell axon regeneration and pathfinding in whole mouse tissue after injury

Injured retinal ganglion cell (RGC) axons do not regenerate spontaneously, causing loss of vision in glaucoma and after trauma. Recent studies have identified several strategies that induce long distance regeneration in the optic nerve. Thus, a pressing question now is whether regenerating RGC axons can find their appropriate targets. Traditional methods of assessing RGC axon regeneration use histological sectioning. However, tissue sections provide fragmentary information about axonal trajectory and termination. To unequivocally evaluate regenerating RGC axons, here we apply tissue clearance and light sheet fluorescence microscopy (LSFM) to image whole optic nerve and brain without physical sectioning. In mice with PTEN/SOCS3 deletion, a condition known to promote robust regeneration, axon growth followed tortuous paths through the optic nerve, with many axons reversing course and extending towards the eye. Such aberrant growth was prevalent in the proximal region of the optic nerve where strong astroglial activation is present. In the optic chiasms of PTEN/SOCS3 deletion mice and PTEN deletion/Zymosan/cAMP mice, many axons project to the opposite optic nerve or to the ipsilateral optic tract. Following bilateral optic nerve crush, similar divergent trajectory is seen at the optic chiasm compared to unilateral crush. Centrally, axonal projection is limited predominantly to the hypothalamus. Together, we demonstrate the applicability of LSFM for comprehensive assessment of optic nerve regeneration, providing in-depth analysis of the axonal trajectory and pathfinding. Our study indicates significant axon misguidance in the optic nerve and brain, and underscores the need for investigation of axon guidance mechanisms during optic nerve regeneration in adults.

Segregation of Ipsilateral Retinal Ganglion Cell Axons at the Optic Chiasm Requires the Shh Receptor Boc

The pattern of contralaterally and ipsilaterally projecting retinal ganglion cell (RGC) axons at the optic chiasm is essential for the establishment of binocular vision. Contralateral axons cross the chiasm midline as they progress from the optic nerve to the optic tract. In contrast, ipsilateral axons deviate from the chiasm and continue in the ipsilateral optic tract, avoiding the chiasm midline. The molecular mechanism underlying this phenomenon is not completely understood. Here we show that the Sonic Hedgehog (Shh) receptor Boc is enriched in ipsilateral RGCs of the developing retina. Together with the presence of Shh at the midline, this complementary expression pattern led us to hypothesize that Shh might repel ipsilateral RGC axons at the chiasm. Consistent with this hypothesis, we found that only Boc-positive RGC axons retract in vitro in response to Shh and that this response is lost in Boc mutant RGCs. In vivo, we show that Boc is required for the normal segregation of ipsilateral axons at the optic chiasm and, conversely, that Boc expression in contralateral RGCs prevents their axons from crossing the optic chiasm. Together, these results suggest that Shh repels ipsilateral RGC axons at the optic chiasm via its receptor Boc. This work identifies a novel molecular pathway required for the segregation of axons at the optic chiasm.

Specificity and Sufficiency of EphB1 in Driving the Ipsilateral Retinal Projection

At the optic chiasm, retinal ganglion cell (RGC) axons make the decision to either avoid or traverse the midline, a maneuver that establishes the binocular pathways. In mice, the ipsilateral retinal projection arises from RGCs in the peripheral ventrotemporal (VT) crescent of the retina. These RGCs express the guidance receptor EphB1, which interacts with ephrin-B2 on radial glia cells at the optic chiasm to repulse VT axons away from the midline and into the ipsilateral optic tract. However, because VT RGCs express more than one EphB receptor, the sufficiency and specificity of the EphB1 receptor in directing the ipsilateral projection is unclear. In this study, we use in utero retinal electroporation to demonstrate that ectopic EphB1 expression can redirect RGCs with a normally crossed projection to an ipsilateral trajectory. Moreover, EphB1 is specifically required for rerouting RGC projections ipsilaterally, because introduction of the highly similar EphB2 receptor is much less efficient in redirecting RGC fibers, even when expressed at higher surface levels. Introduction of EphB1-EphB2 chimeric receptors into RGCs reveals that both extracellular and juxtamembrane domains of EphB1 are required to efficiently convert RGC projections ipsilaterally. Together, these data describe for the first time functional differences between two highly similar Eph receptors at a decision point in vivo, with EphB1 displaying unique properties that efficiently drives the uncrossed retinal projection.

Segregated hemispheric pathways through the optic chiasm distinguish primates from rodents

At the optic chiasm retinal fibers either cross the midline, or remain uncrossed. Here we trace hemispheric pathways through the marmoset chiasm and show that fibers from the lateral optic nerve pass directly toward the ipsilateral optic tract without any significant change in fiber order and without approaching the midline, while those from medial regions of the nerve decussate directly. Anterograde labeling from one eye shows that the two hemispheric pathways remain segregated through the proximal nerve and chiasm with the uncrossed confined laterally. Retrograde labeling from the optic tract confirms this. This clearly demonstrates that hemispheric pathways are segregated through the primate chiasm.Previous chiasmatic studies have been undertaken mainly on rodents and ferrets. In these species there is a major change in fiber order pre-chiasmatically, where crossed and uncrossed fibers mix, reflecting their embryological history when all fibers approach the midline prior to their commitment to innervate either hemisphere. This pattern was thought to be common to placental mammals. In marsupials there is no change in fiber order and uncrossed fibers remain confined laterally through nerve and chiasm, again, reflecting their developmental history when all uncrossed fibers avoid the midline. Recently it has been shown that this distinction is not a true dichotomy between placental mammals and marsupials, as fiber order in tree shrews and humans mirrors the marsupial pattern.Architectural differences in the mature chiasm probably reflect different developmental mechanisms regulating pathway choice. Our results therefore suggest that both the organization and development of the primate optic chiasm differ markedly from that revealed in rodents and carnivores.

Chiasm formation in man is fundamentally different from that in the mouse

At the optic chiasm axons make a key binary decision either to cross the chiasmal midline to innervate the contralateral optic tract or to remain uncrossed and innervate the ipsilateral optic tract. In rodents, midline interactions between axons from the two eyes are critical for normal chiasm development. When one eye is removed early in development the hemispheric projections from the remaining eye are disrupted, increasing the crossed projection at the expense of the uncrossed. This is similar to the abnormal decussation pattern seen in albinos. The decussation pattern in marsupials, however, is markedly different. Early eye removal in the marsupial has no impact on projections from the remaining eye. These differences are related to the location of the uncrossed projection through the chiasm. In rodents, axons that will form the uncrossed projection approach the chiasmal midline, while in marsupials they remain segregated laterally through the chiasm. Histological analysis of the optic chiasm in man provides anatomical evidence to suggest that, unlike in rodents, uncrossed axons are confined laterally from the optic nerve through to the optic tract and do not mix in each hemi-chiasm. This is a pattern similar to that found in marsupials. Electrophysiological evidence in human anophthalmics shows that the failure of one eye to develop in man has no impact on the hemispheric projections from the remaining eye. This strongly suggests that the mechanisms regulating chiasmal development in man differ from those in rodents, but may be similar to marsupials. This implies that optic chiasm formation in rodents and ferrets is not common to placental mammals in general.

The winged helix transcription factor Foxg1 facilitates retinal ganglion cell axon crossing of the ventral midline in the mouse.

During normal development, retinal ganglion cells (RGCs) project axons along the optic nerve to the optic chiasm on the ventral surface of the hypothalamus. In rodents, most RGC growth cones then cross the ventral midline to join the contralateral optic tract; those that do not cross join the ipsilateral optic tract. Contralaterally projecting RGCs are distributed across the retina whereas ipsilaterally projecting RGCs are concentrated in temporal retina. The transcription factor Foxg1 (also known as BF1) is expressed at several key locations along this pathway. Analysis of Foxg1 expression using lacZ reporter transgenes shows that Foxg1 is normally expressed in most, if not all, nasal RGCs but not in most temporal RGCs, neither at the time they project nor earlier in their lineage. Foxg1 is also expressed at the optic chiasm. Mice that lack Foxg1 die at birth and, although the shape of their eyes is abnormal, their retinas still project axons to the brain via the optic chiasm. Using anterograde and retrograde tract tracing, we show that there is an eightfold increase in the ipsilateral projection in Foxg1-/- embryos. The distributions of cells expressing the transcription factors Foxg1 and Nkx2.2, and cell-surface molecules Ephb2, ephrin B2 and SSEA-1 (Fut4) have been correlated to the normally developing retinothalamic projection and we show they are not much altered in the developing Foxg1-/- retina and optic chiasm. As much of the increased ipsilateral projection in Foxg1-/- embryos arises from temporal RGCs that are unlikely to have an autonomous requirement for Foxg1, we propose that the phenotype reflects at least in part a requirement for Foxg1 outwith the RGCs themselves, most likely at the optic chiasm.

Axon routing at the optic chiasm after enzymatic removal of chondroitin sulfate in mouse embryos.

The effects of removing chondroitin sulfate from chondroitin sulfate proteoglycan molecules on guidance of retinal ganglion cell axons at the optic chiasm were investigated in a brain slice preparation of mouse embryos of embryonic day 13 to 15. Slices were grown for 5 hours and growth of dye-labeled axons was traced through the chiasm. After continuous enzymatic digestion of the chondroitin sulfate proteoglycans with chondroitinase ABC, which removes the glycosaminoglycan chains, navigation of retinal axons was disrupted. At embryonic day 13, before the uncrossed projection forms in normal development, many axons deviated from their normal course, crossing the midline at aberrant positions and invading the ventral diencephalon. In slices from embryonic day 14 embryos, axons that would normally form the uncrossed projection at this stage failed to turn into the ipsilateral optic tract. In embryonic day 15 slices, enzyme treatment caused a reduction of the uncrossed projection that develops at this stage. Growth cones in enzyme-treated slices showed a significant increase in the size both before and after they crossed the midline. This indicates that responses of retinal axons to guidance signals at the chiasm have changed after removal of the chondroitin sulfate epitope. We concluded that the chondroitin sulfate moieties of the proteoglycans are involved in patterning the early phase of axonal growth across the midline and at a later stage controlling the axon divergence at the chiasm.

A Key Role for GAP-43 in the Retinotectal Topographic Organization

To have a proper spatial visual perception, vertebrate retinal ganglion cells connect to their brain targets in a highly ordered fashion. The molecular bases for such topographic retinotectal connection in mammals still remain largely unknown. Using the gene knock-out approach in mice, we report here a key role for the GAP-43 growth cone protein in the development of the visual system. In mice bearing a targeted disruption of GAP-43 exon 1, a high proportion of retinal ganglion cell (RGC) axons was found to grow abnormally into the ipsilateral optic tract and into the hypothalamus. After leaving the optic chiasm during development, the GAP-43-deficient RGC axons generally follow the optic tracts but are unable to form proper terminal zones in the lateral geniculate nucleus. Moreover, in the superior colliculus, RGC axons lacking GAP-43 are intermingled. These results suggest an essential role for GAP-43 in development of the topographic retinotectal connection.

A glial palisade delineates the ipsilateral optic projection in Monodelphis.

In developing marsupials, the path taken through the optic chiasm by ipsilaterally projecting retinal ganglion cells is complicated. Just prior to entry into the chiasm, ganglion cells destined for the ipsilateral optic tract separate from the remainder of axons by turning abruptly downwards to take a position in the ventral part of the optic nerve. In this report, it is shown that a discrete population of about 10-15 large glial cells transiently form a linear array across the prechiasmatic part of the optic nerve, precisely at this axon turning point. The distinct morphology of these cells and their novel location may reflect a specialized role in axon guidance.

Chiasmatic specificity in the regenerating mammalian optic nerve.

The mammalian central nervous system is capable of regenerating; however, there is no evidence that the regenerating axons can navigate along their normal pathways and reestablish topographically organized projections: essential for functional return of vision. Here retinal ganglion cells in the opossum Monodelphis were birthdated with tritiated thymidine on the sixth postnatal day (P6), before being lesioned in the temporal retina at P8. Retrograde tracing with horseradish peroxidase injected into the ipsilateral optic tract at P24 showed that the temporal crescent had reformed behind the retinal lesion. By comparisons of cell and thymidine counts from lesioned and control regions of retina, it was estimated that about 40% of the normal number of ganglion cells are able to regenerate into the ipsilateral optic tract following a lesion in the temporal retina at P8. A clear line of decussation (separation of ipsilateral and contralateral projections) reformed in the lesioned temporal retina and regenerating ganglion cells labeled with DiI were turned at appropriate points on passing through the optic chiasm. This is evidence of chiasmatic specificity with regard to lesioned retinal ganglion cells regenerating into the ipsilateral optic tract.

NMDAR1-like immunoreactive fibers appear in the ipsilateral optic tract during optic nerve regeneration in Rana pipiens

N-Methyl- d-aspartate receptor subunit 1-like immunoreactivity (NMDAR1-LI) was investigated in the brain of Rana pipiens during optic nerve regeneration. Following unilateral optic-nerve crush, frogs were tested for prey-catching and optokinetic nystagmus responses to assess return of visual function. At 1, 2, 3 and 5 months after the surgery, NMDAR1-LI was assessed in central visual pathways. At 3 and 5 months, conspicuous ipsilateral NMDAR1-LI fibers were detected in the thalamic and pretectal nuclei, and the time of their appearance coincided with the onset of behavioral recovery. Also, only ipsilateral retinorecipient layers in the optic tectum showed increased NMDAR1-LI during optic nerve regeneration. These results suggest that NMDA receptors may be present on retinal ganglion cell axons and terminals that have been misrouted during regeneration.

The Pax protein Noi is required for commissural axon pathway formation in the rostral forebrain.

No-isthmus (Noi) is a member of the zebrafish Pax family of transcriptional regulators that is expressed in restricted domains of the developing CNS. In the developing eye and optic nerve, the Noi+ cells are primitive glial cells that line the choroid fissure and optic stalk/nerve to its junction with the optic tract. This pattern of Noi expression is retained in the adult, defining the optic nerve astroglia, which wrap the left and right nerves separately at the midline, thus forming the bodily crossed optic chiasm found in fish. In embryos carrying mutations in the noi gene, the choroid fissure fails to close, glial cells of the optic nerve fail to differentiate and optic axons exhibit abnormal trajectories exiting the eye and at the midline of the diencephalon. Optic axons select inappropriate pathways into the contralateral optic nerve, rostrally towards the anterior commissure and along the ipsilateral optic tract. Noi+ cells also border the pathway of axons in the postoptic commissure, which is located adjacent to the optic chiasm. These postoptic commissural axons are defasciculated and also exhibit pathfinding defects in noi- embryos. These results indicate that Noi is required in cells that line the pathways taken by optic and non-optic commissural axons for guidance across the midline of the diencephalon. We find that expression of two members of the Netrin family of axon guidance molecules and the signalling protein Sonic hedgehog is disturbed in noi- embryos, whereas several members of the Eph family of receptors and ligands show no obvious alterations in expression at the diencephalic midline.

The first retinal axon growth in the mouse optic chiasm: axon patterning and the cellular environment

The retinofugal pathway is a useful model for axon guidance because fibers from each eye project to targets on both sides of the brain. Studies using static and real time analyses in mice at E15-17 demonstrated that uncrossed axons from ventrotemporal retina diverge from crossed axons in the optic chiasm, where specialized resident cells may direct divergence. Other studies, however, suggest that pioneering uncrossed retinal axons derive from a different retinal region, take a different course, and enter the ipsilateral optic tract independent of fiber-fiber interactions. We examine these differences by dye-labeling the earliest optic axons and immunocytochemically identifying cells in their path. The first optic axons arising from dorsocentral retina, enter the diencephalon at E12.5. All axons initially grow caudally, lateral to a radial glial palisade. In contrast to later growing axons, early uncrossed axons enter the ipsilateral optic tract directly. Crossed axons enter the glial palisade and course medially, then anteriorly, in a pathway corresponding to the border of an early neuronal population that expresses SSEA-1, CD44, and beta-tubulin. Axon patterning occurs independent of fiber-fiber interactions from both eyes, as the first uncrossed axons enter the optic tract before crossed ones from opposite eye. These analysis, in conjunction with our previous studies during the principal period of retinal axon growth in the diencephalon, suggest that the adult visual projection arises from age-dependent variations in the types and relative contribution of cues along the path through the emerging optic chiasm.

Genetic control of retinal projections in inbred strains of albino mice.

Mutations in the tyrosinase gene are often associated with a misrouting of retinal ganglion cell axons at the optic chiasm. In albinos, tyrosinase activity is lost and some ganglion cell axons that would normally project into the ipsilateral optic tract instead cross midline and project into the contralateral tract. The developmental mechanisms that cause this modification in neuronal connectivity are unknown. In this study, we screened six diverse strains of albino mice (strains 129, A, AKR, BALB/c, C57BL/6-c/c, and CD-1) to discover genetically determined variations and possible gene loci that might affect the severity of the albino decussation abnormality. Ganglion cells were retrogradely labeled with horseradish peroxidase, and the ipsilaterally and contralaterally projecting cells were counted. The average number of ipsilaterally projecting ganglion cells in the six albino strains varies from 1,000 to 1,300. Despite this variation, 1.8-1.9% of the total population projects ipsilaterally in each strain. In comparison, 2.8% project ipsilaterally in the pigmented strain, C57BL/6(-)+/+. However, the percentage of displaced, ipsilaterally projecting cells varies substantially among albino strains--from a low of 4% in strain CD-1 to a high of nearly 10% in C57BL/6-c/c. We conclude that even with large differences in genetic background and in absolute numbers of ganglion cells, there is no appreciable variation in the magnitude of decussation error among albino mice. The consistent effect of null alleles at tyrosinase suggests a comparably tight linkage between the biochemical activity of this enzyme and the mechanisms that control decussation phenotype.

Analysis of the retinas and optic nerves of achiasmatic Belgian sheepdogs.

An autosomal recessive mutation carried in a family of black Belgian sheepdogs eliminates the optic chiasm--all retinal ganglion cell axons extend directly into the ipsilateral optic tract. One key issue we are trying to resolve is whether the retina or the chiasm is the principal site of mutant gene action. In this study, we have examined retinas of mutants to discover any associated changes in retinal structure. Retinas of mutant animals are relatively normal. Inner and outer nuclear layers are qualitatively indistinguishable from those of normal dogs. The principal difference is that the area centralis of mutants is smaller and had a lower peak ganglion cell density than that of normal dogs (8,100 vs 10,500/mm2, P < 0.05). This mutant phenotype is similar to that seen in retinas of Siamese cats and albino ferrets. Beyond area centralis, the central-to-peripheral gradient in ganglion cell density is normal in mutants. The size of the optic nerves, density of axons, and total number of axons do not differ between mutant and normal dogs. One of three mutant dogs had a small abnormal optic chiasm. Retrograde labeling of ganglion cells demonstrated that the residual crossed projection originated from cells in a widespread region in nasal retina and not solely from the peripheral nasal region, as might be expected of an anti-albino. Although our analysis does not rule out the retina as a site of mutant gene action, the modest differences between mutant and normal retinas suggest that the mutation either acts outside the retina or exerts a highly specific effect on ganglion cell trajectories alone.