Abstract
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.
Mammalian optic chiasm
The retinofugal fibres in the mammalian visual system make a binary decision to either cross the chiasmal midline and project to the contralateral hemisphere or remain uncrossed and project to the ipsilateral hemisphere. The percentage of fibres that remain uncrossed varies between species depending upon how lateral the eyes are placed in the head. This partial decussation of optic fibres at the chiasm forms the basis for normal binocular vision.
The developmental mechanisms that determine the choice of projection in rodents and ferrets are similar. In rodents and ferrets the retinotopic order present in the optic nerve is lost before the nerves fuse at the anterior chiasm1, 2, 3 and the two projections from each eye mix through each hemi-chiasm (Figure 1).4, 5, 6
The marsupial chiasm is distinctly different from that in the rodent and ferret. The architecture of the chiasm is a central core and two lateral appendages. Axonal projections destined for different hemispheres remain strictly segregated along the complete length of the optic nerve and through each hemi-chiasm (Figure 2). Retinal ganglion cell axons destined for the ipsilalateral hemisphere never approach the chiasmal midline and remain confined laterally in the proximal optic nerve and chiasm. In the chiasm they course through the lateral appendages, which are segregated from the contralaterally projecting axons by astrocytic processes.7, 8
Primate optic chiasm
There have been very few examinations of fibre order through the human optic chiasm. However, the results obtained remain controversial. One of the earliest studies by Wilbrand and Saenger9 showed that some axons located laterally in the nerve cross the chiasmal midline and that many crossed axons coursed through the proximal contralateral nerve before approaching the optic tract. However, this analysis was undertaken in tissue from a subject who had lost one eye 24 years before death. Clinical studies cast further light on patterns of fibre organisation through the human optic chiasm. Patients with pituitary tumours have a suprasellar extension from the pituitary fossa, which gives rise to central chiasmal compression. This primarily disrupts the crossed projection, while aneurysms impinging on the lateral chiasm primarily disrupt uncrossed axons.10, 11 Such data are consistent with at least a partial separation of the two projections.
Fibres patterns in the non-human primate have been studied more extensively.12, 13, 14, 15 Horton12 examined anterograde labelling patterns through the primate chiasm and showed that the findings described by Wilbrand and Saenger9 in the human were an artefact resulting from neuronal degeneration following monocular enucleation. These data12 supported a number of other studies undertaken in Old World Primates, suggesting that the two hemispheric projections from each eye are largely segregated through the chiasm, with the uncrossed projection confined laterally, similar to that seen in the marsupial. Early studies on the Macaque monkey induced retinal lesions at specific locations to trace the patterns of nerve fibre degeneration through the optic nerve and chiasm. The studies confirmed that temporal retinal lesions result in degeneration confined to the lateral optic nerve and lateral chiasmatic regions alone. Lesions of the nasal retina, that have no involvement from axons originating from the temporal region, result in degeneration only in the medial or central optic nerve and in the central chiasmatic regions.13, 14 Further studies by Naito15 on the Macaque, showed that when retinal ganglion cells in the temporal retina are labelled following small tracer injections into the thalamus, the labelled axons course laterally through the chiasm, while the chiasmatic pathways of more centrally located ganglion cells do not enter this region. These data suggest that the fibre architecture of the primate optic chiasm is consistent with that seen in the marsupial.
Monocular enucleation studies
It appears that there may be at least two structural forms to the mammalian chiasm; one present in rodents and ferrets and the other in marsupials and perhaps man. Monocular enucleation studies have also shown that the developmental mechanisms of optic chiasm formation are fundamentally different in these animals. In rodents and ferrets, where crossed and uncrossed fibres are intermingled at the chiasmal midline, monocular enucleation early in development reduces the uncrossed projection in favour of the crossed.16, 17 This is similar to the fibre pattern found in albinism, where disruption of melanin synthesis, due to a mutation of the Tyrosinase gene, results in an abnormal projection of the retinofugal fibres at the optic chiasm (Figure 3).18 However, in marsupials, where uncrossed axons are segregated laterally and do not approach the chiasmal midline, early eye removal has no impact on the projections from the remaining eye.19 Hence, there are at least two separate mechanisms regulating chiasm formation. One in rodents and ferrets where midline interactions are significant, and another in marsupials where they are not.
Fibre patterns in the human optic chiasm
Rodent and ferret models of chiasm development have been regarded as typical of most mammals, including man.20, 21, 22, 23 However, there is evidence that the human chiasm is fundamentally different. A recent study by Neveu et al24 showed that the human optic chiasm has two spatially distinct retinal axon trajectory patterns that probably represent the course of the crossed and uncrossed hemispheric projections.
Histological analysis of human nerve fibre patterns
Histological analysis of nerve fibres in the optic chiasm was carried out to investigate the decussation pattern of the visual pathways in the human.24 Fibres were silver-stained and the fibre patterns at the proximal optic nerve, chiasm and distal optic tract were examined. Detailed analysis of these regions demonstrated that the human optic chiasm contains two spatially distinct retinal axon trajectory patterns that probably represent the course of the crossed and uncrossed hemispheric projections (Figure 4). These appear to be largely separate, with the uncrossed projection confined laterally, while the crossed projection occupies more central locations. Groups of axons in the central region are interdigitated in regular plaits across the full length of the midline, demonstrating that axons from each eye intermingle in this region as they course through to the contralateral optic tract. Axons located laterally could be traced in clear parallel lines through from the junction with the nerve towards the optic tract, and at no point did they appear to deviate from this lateral region and approach the midline (Figure 4). However, there was no obvious morphological feature separating the two projections as found in the marsupial.7
Further, there is no obvious change in axon order in the proximal optic nerve that might represent a shift away from the retinotopic pattern found along the length of the optic nerve. This is consistent with the notion that position alone may influence pathway choice rather than interactions at the midline. The fibre patterns seen in humans are consistent with axon patterns found in marsupials, but not those found in rodents and ferrets.4, 6, 7, 22, 25
Electrophysiological analysis of cortical hemispheric projections in anophthalmics
Unlike rodents and ferrets, which have a relatively small number of optic axons (approximately 110 000)26 and a small uncrossed projection,27, 28 the retinogeniculate pathway in man is large, comprising of approximately 1.1 million optic axons,29, 30, 31 and the chiasmatic pathways from each eye in primates divides almost equally between hemispheres.32 This can be demonstrated using the visual evoked potential (VEP), an electrodiagnostic test that enables objective assessment of the visual pathways, including a representation of the hemispheric projections to the visual cortex. The relative size and timing of the responses recorded over each hemispheric projection gives an indication of the retinocortical fibre decussation pattern at the optic chiasm. Therefore, in the normal, the size and timing of the responses from each hemisphere are symmetrical, demonstrating an equal decussation of the retinocortical fibres to the ipsilateral and contralateral hemisphere. This is very different to the VEP pattern seen in albino patients. In the albino, a larger and faster conducting response is seen in the contralateral hemisphere to the stimulated eye. The responses in the ipsilateral hemisphere are smaller and delayed compared to those in the contralateral hemisphere, demonstrating an abnormal decussation pattern, where the majority of nerve fibres cross the chiasmal midline to innervate the contralateral hemisphere. VEPs therefore can be used to determine if the pattern of decussation in human monocular anophthalmics is similar to that seen in the rodent and ferret or if it is similar to the marsupial.
VEP techniques were used to examine a group of patients with anophthalmia or severe microphthalmia and compare them with age-matched albino and normal controls.24 Anophthalmia is a genetically determined disorder where the patient is born without an eye or a chronically underdeveloped eye.33 It is predominantly due to a mutation in the SOX2 gene,34 although mutational analysis has shown that other genes such as OTX2 and Pax6 have also been implicated in malformation or the absence of an eye at birth. These genes play a significant role in the development of the eye.35
Anophthalmic patients were examined to study optic chiasm development when only one eye was present at birth, this situation being analogous to that of early unilateral eye removal in animals. However, it could be argued that in anophthalmic/severe microphthalmic subjects, two optic nerves were present at some early stage of development, during which the ground plan for chiasm formation was established, but that one was subsequently degenerated. Although possible, ultrasound scanning and orbital examination during surgery revealed no significant anatomical or histological remnant of viable neural tissue in the socket. Also, the failure of the orbit to develop without surgical intervention is an indication that an eye was not present. Even in those with severe microphthalmia rather than anophthalmia, a significant optic nerve is rarely formed. In addition, normal retinal function was demonstrated in the remaining eye of all individuals by recording the electroretinogram from this eye.
The VEP in anophthalmic and severely microphthalmic patients is symmetrical, reflecting a normal chiasmatic decussation of the nerve fibres from the eye to the brain, in the absence of the contralateral eye.24 There was no evidence of an asymmetrical albino-like VEP in any of these patients, suggesting that normal development of the human optic chiasm, unlike the rodent and ferret, does not require the interaction of nerve fibres from both eyes to determine the correct choice of projection. Development of the human chiasm is unaffected by the absence of the contralateral nerve fibres. Although the methods of analysis differ, data from the human and the marsupial show a consistency that distinguishes them from rodents and the ferret.
Discussion
The mammalian optic chiasm can be grouped into at least two basic forms, that seen in rodents and ferrets and that seen in marsupials (Figure 5). In rodents and ferrets retinotopic order is lost in the proximal nerve where there is a major change in axon order, and axons approach the midline before deciding whether to decussate or turn away and innervate the ipsilateral hemisphere.4, 6, 36 Two mechanisms may influence this pattern of decussation. First, there are interactions between axons from the two eyes at the midline region, and second, there are interactions between midline glia.5, 37 The importance of the first mechanism is confirmed by monocular enucleation studies in these animals where the removal of one eye results in an albino pattern from the remaining eye.16, 17 Different mechanisms are described in marsupials. There is no change in the pre-chiasmatic axon order and axons that form the uncrossed projection remain confined laterally through the chiasm and are segregated by astrocytic processes.7 Similar patterns are found in the tree shrew.38 Therefore unlike the rodent, no axons destined for the ipsilateral hemisphere approach the chiasmal midline and it is the spatial orientation of these fibres, such as their position in the nerve determines their choice of projection. This is supported by the observations of early eye removal in marsupials over a range of developmental stages that has no impact on the projections from the remaining eye,19 similar to the observations reported in man.
The segregated pattern of hemispheric projections through the mammalian chiasm were first identified in marsupials and tree shrews.7, 38 These animals represent the prototypic mammalian form, which was a shrew like marsupial.39 Rodents and ferrets branch as separate groups at a later stage. Hence, it is probable that the segregated pattern of hemispheric projections found in the chiasm of primates including man, predominates among mammals and lower vertebrates, and studies in progress support this.
The optic chiasm is a popular model for studying axon guidance. Research on its development has been a key area of recent research activity, because at this location optic axons make a binary choice of whether to cross the midline or not. Chiasm formation in rodents is markedly different from that in man. Recent studies strongly suggest that the architecture of this region and the mechanisms that regulate its development differ significantly between the two. This is of particular importance as chiasm development in the mouse is thought to reflect that in man. Studies in the marsupial and man suggest otherwise; therefore, caution should be exercised when attempting to extrapolate from rodents to higher mammals.
References
Colello SJ, Guillery RW . The changing pattern of fibre bundles that pass through the optic chiasm of mice. Eur J Neurosci 1998; 10: 3653–3663.
Fitzgibbon T, Reese BE . Organization of retinal ganglion cell axons in the optic fiber layer and nerve of fetal ferrets. Vis Neurosci 1996; 13: 847–861.
Guillery RW, Walsh C . Changing glial organization relates to changing fiber order in the developing optic nerve of ferrets. J Comp Neurol 1987; 265: 203–217.
Baker GE, Jeffery G . Distribution of uncrossed axons along the course of the optic nerve and chiasm of rodents. J Comp Neurol 1989; 289: 455–461.
Marcus RC, Mason CA . The first retinal axon growth in the mouse optic chiasm: axon patterning and the cellular environment. J Neurosci 1995; 15: 6389–6402.
Baker GE . Prechiasmatic reordering of fibre diameter classes in the retinofugal pathway of ferrets. Eur J Neurosci 1990; 2: 24–33.
Jeffery G, Harman AM . Distinctive pattern of organisation in the retinofugal pathway of a marsupial: II. Optic chiasm. J Comp Neurol 1992; 325: 57–67.
Harman AM, Jeffery G . Development of the chiasm of a marsupial, the quokka wallaby. J Comp Neurol 1995; 359: 507–521.
Wilbrand HL, Saenger A . Die Neurologie des Auges. EinHhandbuch fur Nerven und AUGENARZTE: Bergman, Wiesbaden, 1904.
Day AL . Aneurysms of the ophthalmic segment. A clinical and anatomical analysis. J Neurosurg 1990; 72: 677–691.
Holder GE . Chiasmal and retrochiasmal lesions. In: Heckenlively JR, Arden GB (eds) Principles and Practice of Clinical Electrophysiology of Vision. Mosby Year Book: St Louis, 1991 pp 557–564.
Horton JC . Wilbrand's knee of the primate optic chiasm is an artefact of monocular enucleation. Trans Am Ophthalmol Soc 1997; 95: 579–609.
Hoyt WF, Luis O . Visual fiber anatomy in the infrageniculate pathway of the primate. Arch Ophthalmol 1962; 68: 94–106.
Hoyt WF, Luis O . The primate chiasm. Details of visual fiber organization studied by silver impregnation techniques. Arch Ophthalmol 1963; 70: 69–85.
Naito J . Retinogeniculate projection fibers in the monkey optic nerve: a demonstration of the fiber pathways by retrograde axonal transport of WGA-HRP. J Comp Neurol 1989; 284: 174–186.
Godement P, Salaun J, Metin C . Fate of uncrossed retinal projections following early or late prenatal monocular enucleation in the mouse. J Comp Neurol 1987; 255: 97–109.
Guillery RW . Early monocular enucleations in fetal ferrets produce a decrease of uncrossed and an increase of crossed retinofugal components: a possible model for the albino abnormality. J Anat 1989; 164: 73–84.
Jeffery G . The albino retina: an abnormality that provides insight into normal retinal development. Trends Neurosci 1997; 20: 165–169.
Taylor JS, Guillery RW . Does early monocular enucleation in a marsupial affect the surviving uncrossed retinofugal pathway? J Anat 1995; 186 (Part 2): 335–342.
Herrera E, Brown L, Aruga J, Rachel RA, Dolen G, Mikoshiba K et al. Zic2 patterns binocular vision by specifying the uncrossed retinal projection. Cell 2003; 114: 545–557.
Plump AS, Erskine L, Sabatier C, Brose K, Epstein CJ, Goodman CS et al. Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Neuron 2002; 33: 219–232.
Reese BE, Baker GE . The course of fibre diameter classes through the chiasmatic region in the ferret. Eur J Neurosci 1990; 2: 34–49.
Williams SE, Mason CA, Herrera E . The optic chiasm as a midline choice point. Curr Opin Neurobiol 2004; 14: 51–60.
Neveu MM, Holder GE, Ragge NK, Sloper JJ, Collin JR, Jeffery G . Early midline interactions are important in mouse optic chiasm formation but are not critical in man: a significant distinction between man and mouse. Eur J Neurosci 2006; 23: 3034–3042.
Harman AM, Jeffery G . Distinctive pattern of organisation in the retinofugal pathway of a marsupial: I. Retina and optic nerve. J Comp Neurol 1992; 325: 47–56.
Potts RA, Dreher B, Bennett MR . The loss of ganglion cells in the developing retina of the rat. Brain Res 1982; 255: 481–486.
Jeffery G, Cowey A, Kuypers HG . Bifurcating retinal ganglion cell axons in the rat, demonstrated by retrograde double labelling. Exp Brain Res 1981; 44: 34–40.
Morgan JE, Henderson Z, Thompson ID . Retinal decussation patterns in pigmented and albino ferrets. Neuroscience 1987; 20: 519–535.
Bruesch SR, Arey LB . The number of myelinated and unmyelinated fibres in the optic nerve of vertebrates. J Comp Neurol 1942; 77: 631.
Polyak SL . The Retina. University of Chicago Press: Chicago, 1941.
Quigley HA, Addicks EM, Green WR . Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol 1982; 100: 135–146.
Fukuda Y, Sawai H, Watanabe M, Wakakuwa K, Morigiwa K . Nasotemporal overlap of crossed and uncrossed retinal ganglion cell projections in the Japanese monkey (Macaca fuscata). J Neurosci 1989; 9: 2353–2373.
Morrison D, FitzPatrick D, Hanson I, Williamson K, van HV, Fleck B et al. National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology. J Med Genet 2002; 39: 16–22.
Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L, de Sanctis U et al. SOX2 anophthalmia syndrome. Am J Med Genet A 2005; 135: 1–7.
Hever AM, Williamson KA, van Heyningen V . Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. Clin Genet 2006; 69: 459–470.
Jeffery G . Distribution of uncrossed and crossed retinofugal axons in the cat optic nerve and their relationship to patterns of fasciculation. Vis Neurosci 1990; 5: 99–104.
Marcus RC, Blazeski R, Godement P, Mason CA . Retinal axon divergence in the optic chiasm: uncrossed axons diverge from crossed axons within a midline glial specialization. J Neurosci 1995; 15: 3716–3729.
Jeffery G, Harman A, Flugge G . First evidence of diversity in eutherian chiasmatic architecture: tree shrews, like marsupials, have spatially segregated crossed and uncrossed chiasmatic pathways. J Comp Neurol 1998; 390: 183–193.
Novacek MJ . Mammalian phylogeny: shaking the tree. Nature 1992; 356: 121–125.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Neveu, M., Jeffery, G. Chiasm formation in man is fundamentally different from that in the mouse. Eye 21, 1264–1270 (2007). https://doi.org/10.1038/sj.eye.6702839
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.eye.6702839
Keywords
This article is cited by
-
Astrocyte derived TSP2 contributes to synaptic alteration and visual dysfunction in retinal ischemia/reperfusion injury
Cell & Bioscience (2022)
-
Case report: Unilateral optic nerve aplasia and developmental hemi-chiasmal dysplasia with VEP misrouting
Documenta Ophthalmologica (2021)
-
Human Pluripotent Stem Cell-Derived Retinal Ganglion Cells: Applications for the Study and Treatment of Optic Neuropathies
Current Ophthalmology Reports (2015)
-
Traumatology of the optic nerve and contribution of crystallins to axonal regeneration
Cell and Tissue Research (2012)