One possibility is that unique guidance cues that are specific to the uncrossed projection might be expressed on RGC axons or within the SC. Alternatively, the same molecular cues might differentially guide ipsilateral and contralateral RGCs. A third possibility is that the ipsilateral projection maps onto the contralateral projection by activity-dependent mechanisms based on the similarity of visual information from both eyes.
We will describe the development of both structures SC and dLGN and for each, review experiments that address the possible mechanisms of integration of ipsilateral and contralateral projections. Retinal ganglion cells are generated between embryonic E days in pigmented mice [ 23 ]. Contralaterally and ipsilaterally projecting RGCs are generated at the same time, though not on the same timetable; cells which cross at the optic chiasm are generated throughout this period, whereas cells that do not cross are generated within ventro-temporal retina mostly between EE16 [ 23 ].
The superior colliculus of the midbrain has an important role in integrating cortical and retinal inputs, and functionally is involved in recognition, localization and responsiveness to novel stimuli Sefton et al. The majority of visually driven input to the superficial layers of the SC is from the retina and the primary visual cortex and, as for the dLGN, mapping of the ipsilateral and contralateral visual projections provides a continuous representation of the visual field even though the inputs are anatomically segregated.
There are also auditory and somatosensory inputs to intermediate and deep SC layers as well as input from secondary visual cortices, parabigeminal nucleus, and a large number of nuclei in the brainstem [ 26 , 27 ]. Major outputs are to the thalamus, the pons, as well as brainstem nuclei and spinal cord segments involved in the control of head and neck movements [ 10 , 26 , 27 , 28 , 29 ]. There are seven layers in the superior colliculus in mammals.
The most superficial three layers primarily receive retinal input: the stratum zonale, stratum griseum superficiale and the stratum opticum [ 26 , 30 , 31 ]. The superficial layers receive also inputs from the visual cortex and the intermediate and deep layers receive input from other cortical areas [ 32 ].
The neurons of the SC in the mouse are produced between EE13, with the most superficial layers being produced last [ 33 ]. Layers resembling those seen in the mature mouse are present by postnatal P day 6 [ 33 , 34 ]. Ipsilateral fibres appear later, around E19 until P3 [ 24 ].
Incoming contralateral [ 36 ] and ipsilateral [ 37 ] axons all extend past their appropriate termination zones and as a result, input is initially scattered and widespread [ 38 ], with only rough retinotopic topography and without segregation of ipsilateral and contralateral fibres. Refinement of the projections topography and eye-specific occurs by the formation along the rostrocaudal axis of interstitial branches that are targeted to the location of the topographically appropriate termination zone [ 39 ]. These branches form dense arborisations within the superficial grey layer of the SC and any ectopic branches and overshooting axons are removed [ 41 , 42 , 43 , 44 ].
Pruning begins to occur by P4 and is complete by P8-P11 for both contralateral and ipsilateral projections [ 24 , 37 ].
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As a result, the retinocollicular map is established and refined in the first two postnatal weeks [ 45 ] s uch that temporal retinal axons project to rostral SC and nasal retinal axons project to caudal SC. The ipsilateral axons terminate in small patches that are within the rostro-medial superficial grey but located slightly deeper than the contralaterally projecting axons [ 10 ]. There is overlap of contralateral and ipsilateral fibres during the first postnatal week; segregation occurs before the eyes open and is complete by the end of the second postnatal week P [ 41 , 46 ] with the ipsilateral terminals being restricted to an isolated roughly trapezoid shape patch within the contralateral terminals [ 47 , 48 ].
Carnivorous mammals such as cats, ferrets and shrews, as well as primates, have more complex layering and segregation within the dLGN based on the characteristics of the RGC inputs [ 49 ], reflecting their more sophisticated thalamo-cortical visual processing circuitries. From the LGN, information from both eyes is carried to neurons in layer 4 of primary visual cortex.
In cats and primates [ 50 , 51 ], ipsilateral and contralateral inputs are segregated into ocular dominance columns in layer 4 throughout V1. By contrast in rodents, only lateral visual cortex receives binocular inputs with the medial part being purely monocular [ 52 , 53 , 54 ]. The circuitry of the visual system is established via complex guidance mechanisms that involve responses to molecular cues, and interactions between projections by activity-dependent mechanisms [ 1 , 55 , 56 ].
During development, newly-generated neurons send out developing axons that are guided in their outgrowth via cues which may be diffusible or cell-surface bound, and which may attract or repulse actively growing processes [ 56 ]. These various molecular cues assist in targeting, axon fasciculation, and the pruning of inappropriate axonal arbours. Targeting is both structural in assisting the axon to locate the correct structure within the brain and detailed so that the connections are to the correct postsynaptic cell in the appropriate cell layer.
In addition, activity dependent pruning further refines the developing projections such that accuracy is maximised [ 57 , 58 , 59 ]. Other guidance cues for example semaphorins, engrailed and L1 are crucial for the contralateral projection [ 60 , 61 , 62 ] In addition other molecules that have been implicated in eye specific segregation and terminal arborisation, but not in fundamental topographic organisation of the ipsilateral projection, such as BDNF, nitric oxide and the NMDA receptor [ 63 , 64 , 65 ] will not be discussed further.
The property which makes ephrins and Teneurins unique and ideally suited to topographic mapping between brain regions is their graded expression patterns.
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This theory predicted that topographic mapping would require unique cytochemical cues expressed by each RGC and its target neuron in the SC. Ephrins are cell-surface bound ligands that bind to Eph receptors, which are receptor tyrosine kinases. The members of the ephrin-A class are linked to the membrane by a glycerophospholipid and the ephrin-B class ligands are transmembrane molecules [ 72 ].
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There are multiple ephrins and Eph receptors in the two classes; with some exceptions [ 73 ], ephrin-As will only bind to EphA receptors though binding within each class is non-specific and ligands are able to bind to multiple receptors [ 70 ]. Ephs and ephrins are expressed during nervous system development by the target tissue and growth cones of the developing axon.
Following Eph-ephrin binding, the growth cone can be attracted primarily through EphB-ephrin-B signalling or repulsed EphA-ephrin-A signalling directing axons into appropriate regions within brain structures and setting up tissue boundaries and internal organisation [ 74 , 75 ]. In addition, both receptors and ligands are found to be expressed in the tissue of origin and in the target cells, further regulating the signal transduction process and sensitivity to target guidance cues [ 80 , 81 , 82 ].
During development retinal ganglion cells make a crucial choice at the chiasm. The partial decussation of retinal axons at the optic chiasm is thought to be due to the action of ephrin-B ligands, specifically ephrin-B2 [ 83 ] which is expressed on specialised radial glial cells that are situated each side of the midline at the base of the third ventricle [ 84 ].
This localised ephrin-B1 at the chiasm causes repulsion of ipsilaterally projecting RGC axons which express EphB1 [ 85 , 86 , 87 ] and as a result they do not cross but remain on the same side of the brain.
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However, EphB triple knockout mice retain some ipsilaterally projecting axons, suggesting that other molecules, such as Nogo [ 88 , 89 ] may also play a role. Within the LGN, ephrin ligands and Eph receptors are expressed as gradients correlating topographic organisation of the contralateral projection [ 41 ]. Graded expression of ephrin ligands was first demonstrated in the tectum of the chick [ 67 , 68 ] and knockout mice subsequently confirmed the key role of these proteins in mapping the contralateral visual projection [ 45 , 90 ]. More recently, a role for ephrins in mapping the ipsilateral projection in the superior colliculus was demonstrated by anatomical tracing and electrophysiological experiments which compared the distribution of ipsilateral and contralateral projections [ 2 ].
The ipsilateral projection was expanded to fill the full extent of the SC and the organisation of the projection was highly abnormal and misaligned with the contralateral one. Furthermore, the study showed a behavioural deficit that could be rescued by blocking the input to one eye, confirming that although small in size, the ipsilateral projection has significant functional impact [ 2 ]. In most species studied to date, the Teneurin family contains four members Ten-m; [ 91 ], which are large transmembrane proteins that are found as homo or heterodimers [ 92 , 93 ].
They are believed to interact with Ten-m molecules on other cells via homophilic or heterophilic interactions [ 92 , 94 ]. Like Ephs and ephrins, Teneurins are expressed as gradients within many regions of the developing brain [ 95 ] and relevant to this chapter, have matching gradients across the interconnected visual brain regions retina, dLGN, SC and visual cortex; [ 3 , 96 ].
However, in contrast to the Ephs and ephrins, very little is known about how the Teneurins exert their guidance activity. In response to binding, Teneurins have several potential signalling methods involving the extracellular and intracellular domains. The C-terminus extracellular domain of Teneurins can be cleaved by furin to produce a peptide with homology to the corticotrophin releasing factor CRF; [ 97 , 98 ] that has been shown to influence neurite extension and anxiety-related behaviours [ 99 , ].
In addition, the intracellular domain has multiple tyrosine phosphorylation sites, calcium binding motifs and two SH3 binding sites, providing opportunities to interact with many signalling pathways as well as the cytoskeleton [ ]. Furthermore, the intracellular domain has been shown to translocate to the nucleus and regulate transcription [ , ].
watch Expression peaks during early postnatal development and is highest in regions of the visual pathway associated with the ipsilateral projection. Aberrant projections were also observed in visual cortex, where ipsilateral input was not restricted to the laterally located binocular zone, but rather formed patches within the monocular region that are reminiscent of ocular dominance domains [ ].
Furthermore, recording from cortical cells confirmed that binocular stimulation leads to functional suppression of mismatched binocular inputs [ ]. This study also examined for the first time the developmental time-course of ipsilateral retinocollicular projections relative to contralateral ones. For the Ephs and ephrins, an important tool used to study this graded expression pattern was the stripe assay, which studied the growth behaviours of RGCs from different retinal locations on substrates made up of collicular membranes [ , ].
Temporal axons were more inhibited than nasal axons, and though they would grow on both anterior and posterior collicular membranes, they showed a preference for anterior membranes, their natural target [ ]. Nasal axons did not show a consistent preference although see [ ]. Perhaps surprisingly, Ten-ms have not been studied in the stripe assay, possibly because the technique has not been used in recent years: although membrane stripe assays provided a foundation for understanding how the retinotopic map develops, there are limitations with these studies.
The artificial in vitr o conditions, sometimes using lysed or non-neuronal cells, did not reproduce the complex environment of the developing brain and may have adversely affected retinal explant outgrowth. These initial studies also failed to identify the importance of the concentration gradient itself [ 69 , , ] or the complexity of the multiple interactions between ephrins and other proteins that have since been elucidated [ 43 , , ].
However, such studies provided the useful background for studying topographical development in vivo. A particular limitation has been in the study of ipsilaterally projecting RGCs which represent such a small proportion of the total RGCs that their behaviour, even if different from that of contralaterally projecting cells, would not have been noted.
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Other Eph transgenic mice have been useful in elucidating the principles of topographic mapping by Ephs, in particular an elegant study by Brown and colleagues which demonstrates the importance of graded expression in point to point mapping [ 69 ]. As reviewed above, the development of the ipsilateral retinocollicular projection is at least in part regulated by molecular guidance cues.
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However, studies that removed one eye at birth have indicated that the contralateral projection has an influence on the development of the ipsilateral projection.