Ординатура / Офтальмология / Английские материалы / Retinal Development_Sernagor, Eglen, Harris, Wong_2006

the current hypothesis is that the majority of mammalian RGCs progress from an early non-stratified stage – characterized by ON–OFF responses and ramification throughout the depth of the IPL – to a mature stratified stage whereupon they respond as strictly ON or OFF cells and dendritic arbors are restricted to corresponding regions of the IPL (Bodnarenko et al., 1995, 1999; Lohmann and Wong, 2001; Stacy and Wong, 2003).

The morphologies of retinal neurons in non-mammalian species are known to be considerably more complex in terms of their stratification patterns (Cajal, 1972; Ammermuller and Kolb, 1995; Wu et al., 2000; Mangrum et al., 2002; Pang et al., 2002; Naito and Chen, 2004). One by-product of this is a veritable explosion in the number of morphological subtypes of retinal neurons encountered in these species. For instance, studies correlating morphology and physiology of retinal neurons in the tiger salamander have found more than 70 amacrine and bipolar cell patterns of stratification (Pang et al., 2002 and Pang et al., 2004, respectively). Interestingly, the physiological data indicate that of the ten IPL sublaminae delineated in the salamander retina; strata 1, 2 and 4 are OFF-responding, 3 and 7 to 10 are ON-responding, and 5 and 6 are ON–OFF. Thus, the physical segregation of ON and OFF channels is not strictly maintained and the overall pattern is not simply one of roughly splitting the IPL into two regions. It will be interesting to determine if the remodelling strategy of overgrowth and retraction, typified for mammalian RGCs, holds for the neuritic maturation of other subtypes of retinal neurons (and/or for different species), and to ascertain functions for the multiple strata found in retinas with such elegantly sublaminated circuitry.

What cellular interrelationships are required to form stratified arborizations in the IPL? Cellular ablation studies have provided insights into this question and to the cellular origins of stratification signals. For instance, RGCs can be induced to degenerate by severing the optic nerve. This approach was used to test whether the stratification patterns of immunolabelled subpopulations of amacrine and bipolar cells depend on the presence of RGCs in rats and ferrets (Gunhan-Agar et al., 2000; Williams et al., 2001, respectively). Despite concomitant effects on the width of the IPL ( 70% the normal width) and amacrine numbers (several subtypes reduced), in the absence of RGC-derived targets all cell types tested formed relatively normal innervation patterns in the IPL. Similarly, in a zebrafish mutant in which RGCs never develop (lakritz), the bistratification pattern of a transgenically defined amacrine cell subpopulation was found to be nearly normal at maturity; showing only circumscribed areas of disruption (Kay et al., 2004). Time-lapse analysis revealed more pronounced abnormalities during the initial phases of IPL formation in lakritz, but the majority of these anomalies appear to resolve over time. Thus, the development of stratified arbor morphologies of bipolar and amacrine cells does not appear to depend on the presence of RGC dendrites. Interestingly, in those regions displaying aberrant amacrine cell stratification in lakritz mutants, a population of ON-stratifying bipolar cell axons (PKCβ1- immunoreactive) appeared to shadow the ectopic laminar patterns of the amacrine cells. This finding suggests that distinct bipolar and amacrine subpopulations are either interdependent regarding sublamination or that bipolar axons seek out cues from amacrine cells. In

addition, it has been shown in several systems that cholinergic amacrine cells stratify prior to most RGCs and bipolar cells (Reese et al., 2001; Gunhan et al., 2002; Drenhaus et al., 2003; Stacy and Wong, 2003). Thus, cholinergic amacrines may be positioned upstream, in a hierarchical sense, providing guidance signals for the bipolar and RGC subtypes that subsequently ramify within the sublaminae that they establish (Bansal et al., 2000). In contrast, excitotoxic ablation of cholinergic amacrines in the postnatal ferret does not disrupt stratification patterns defined by several other neurotransmitter types (Reese et al., 2001). Furthermore, immunotoxin-mediated ablation of cholinergic amacrine cells in postnatal rats does not disrupt bistratification of recoverin-expressing cone bipolar cells (Gunhan et al., 2002). However, whether any of the cell types labelled in these studies actually interact with cholinergic amacrines at the synaptic level is not known. Similar studies performed on definitive sets of synaptic partners are needed to resolve this issue further.

12.4.3 Role of molecular guidance cues

How might molecules be used to specify retinal stratification patterns? One of the most attractive models for how neural circuits form involves unique molecular adhesion profiles that are shared between synaptic partners. Differential adhesion would thereby provide the initial stimulus to stabilize neuritic contacts. Interestingly, a number of cell–cell adhesion molecules are expressed in stratified patterns in the IPL of the retina (Wohrn et al., 1998; Honjo et al., 2000; Drenhaus et al., 2003, 2004). However, direct evidence for this model has been elusive, possibly due to the fact that disruption of cell–cell adhesion molecules often results in a number of pleiotropic effects. Evidence for general repulsive and/or attractive cues is also lacking. However, the distance between retinal synaptic partners is small enough that contact may result from polarized outgrowth alone without the need for positional gradients.

Despite the difficulties inherent in these studies several molecules have been implicated in IPL formation and patterning: Disruption of Plexin function, a cell surface co-receptor that mediates the repulsive effects of Semaphorins, results in a failure of IPL formation in the chick retina (Ohta et al., 1992). Interestingly, individual plexin subfamily members are expressed in amacrine, bipolar and retinal ganglion cell subsets. However, it is not yet known whether this corresponds to expression within individual strata of the IPL. Beyond its role in organizing retinal patterning in general (Matsunaga et al., 1988; Erdmann et al., 2003; Malicki et al., 2003), N-cadherin may function specifically to promote proper targeting and lamination of retinal neurites. A hypomorphic mutation in zebrafish (N-cadRW95), which retains partial N-cadherin function, has been shown to cause defects in amacrine neurite patterning despite the relatively normal appearance of bipolar and retinal ganglion cell morphologies (Masai et al., 2003). However, expression of a dominant negative form in single cells of the frog retina suggests that N-cadherin functions primarily to promote RGC outgrowth while having lesser effect on other retinal cell types (Riehl et al., 1996). Finally, recent evidence implicates two new members of the immunoglobin superfamily as direct sublamination

guidance cues in the chick retina (Yamagata et al., 2002). Sidekicks (1 and 2) have been shown to promote homophilic binding and are expressed in retinal neuron subsets. Like several other immunoglobin family members, Sidekicks are expressed in specific IPL sublaminae suggesting these molecules may serve as laminar adhesion zones. In support of this idea, sidekick-1 overexpression is correlated with stratification patterns that suggest it acts as a laminar-patterning determinant. This study, therefore, provides the first evidence of a molecular ‘matchmaker’ involved in patterning IPL circuitry. Proposed loss of function studies in the mouse should help to resolve several outstanding questions regarding the roles Sidekicks play in retinal development.

Finding irrefutable stratification regulators may prove difficult by reverse genetics methods (e.g. knockout mice) since the factors implicated to date are likely to perform multiple developmental functions. In fact, direct cause and effect relationships become increasingly difficult at the single molecule level as the biological process of interest becomes more complex. Circuit formation may rely heavily on mechanistic redundancies that simply render it unsusceptible to the loss of individual molecular components. One approach, which might provide evidence of singularly critical factors, is forward genetics screening in zebrafish. For instance, transgenic zebrafish with fluorescently labelled retinal neuron subtypes (see Chapter 17), or lamina-specific antibodies (Yazulla and Studholme, 2001) could prove particularly useful in identifying mutants that specifically disrupt sublamination patterns in the IPL.

12.4.4 Role of activity

It is clear that not only molecular cues, but also neuronal activity, in particular synaptic signalling, plays a role in the stratification process. Initial evidence for a role of neuronal activity in regulating the vertical extent of RGC dendrites has been obtained by manipulating synaptic signalling in the postnatal cat retina using 2-amino-4-phosphonobutyric acid (APB), an agonist of the metabotropic glutamate receptor mGluR6. In developing ferrets APB blocks all light-induced activity in ON/OFF RGCs (Wang et al., 2001; note that in the adult only ON bipolar cells express the mGluR6 receptor and consequently APB affects only the activity of the ON pathway). Single intraocular injections of APB in newborn cats delay the stratification of ON and OFF RGCs (Bodnarenko and Chalupa, 1993; Bodnarenko et al., 1995) while long-term APB application prevents stratification completely (Deplano et al., 2004; see also Chapter 14). Therefore, synaptic activity – probably partly resulting from visual stimulation – appears to be required for the stratification of RGC dendrites. Interestingly, the maturation of ON and OFF responses of RGCs is also inhibited by APB applications (Bisti et al., 1998; see also Chapter 14). These studies demonstrate the close relationship between the development of function, such as ON or OFF responses, and the structure of dendrites, namely their segregation into the ON or OFF subregions of the IPL.

Surprisingly, impairing mGluR6 signalling in transgenic mice – where synaptic activity onto RGCs is most likely increased – does not affect stratification. For example, the structural development of dendrites is not affected in mGluR6 knockout mice (Tagawa et al., 1999)

nor in mice lacking the G-protein subunit, Gαo, required for mGluR6 signalling (Dhingra et al., 2000). These findings may indicate that a certain level of glutamatergic activation from presynaptic bipolar cells is required for the segregation of RGC dendrites, whereas the exact pattern of activity may be less critical.

Besides bipolar cells, which provide glutamatergic inputs onto RGCs, various types of amacrine cells also make synaptic connections with ganglion cells. Amacrine cells are present early in retinal development and it has been shown that cholinergic signalling regulates dendritic stratification. In mutant mice that lack the β2 subunit of the nicotinic acetylcholine receptor stratification is delayed (Bansal et al., 2000). More dramatic is the phenotype of acetylcholine esterase knockout mice: stratification of neurites from various cell types in the IPL is severely altered (Bytyqi et al., 2004). Since not all RGC types establish contacts with processes of cholinergic amacrine cells (Stacy and Wong, 2003), it is not surprising that the disruption of cholinergic signalling affects only a subpopulation of RGCs. Other amacrine cell types may influence the development of RGC dendrites as well. However, it is unknown whether RGC dendrites stratify in the complete absence of any specific subset of amacrine cells. In addition, it has not been investigated whether transmitters that are released by different types of amacrine cells (e.g. γ-aminobutyric acid, glycine, or dopamine) may be involved in RGC dendrite stratification.

The fact that synaptic signalling is required for the refinement of the structure of RGC dendrites raises the question whether spontaneous or light-induced activity or both are involved in this process. In fact, vision appears to be important, since dark rearing for one month after birth results in a higher number of ON/OFF neurons and multistratified RGCs in mice compared with normally raised animals (Tian and Copenhagen, 2003). Also the finding that more dorsal lateral geniculate nucleus (dLGN) neurons respond to both increases and decreases of light after dark rearing may be interpreted as a deficit in intraretinal wiring (Akerman et al., 2002). At least two observations suggest that the mean activity of RGCs and their inputs is reduced during dark rearing. (1) Vision increases the spike activity of ferret dLGN neurons, even before eye opening (Akerman et al., 2002). (2) Dark rearing leads to a reduction of spontaneous synaptic events in RGCs of mice during the first postnatal month (Tian and Copenhagen, 2001). Thus, the results from dark rearing experiments further strengthen the conclusion that a certain amount of synaptic activity is required for the stratification of RGC dendrites and the development of selective ON or OFF response patterns of RGCs.

What are the activity-dependent processes that allow neurons to direct or rearrange their processes into specific sublaminae? As described above, RGC dendrites show a high degree of plasticity, which is regulated by synaptic activity. Over time, this dendritic plasticity may convert unspecifically distributed dendrites into laminated structures by selectively pruning the processes that are located in inappropriate layers and stabilizing those in appropriate areas (Fig. 12.4b). Recently, a mechanism has been described that allows RGCs to selectively stabilize single dendritic branches by transmitter-induced local release of Ca2+ from internal stores (Lohmann et al., 2002). Local Ca2+ signals may stabilize those dendritic branches that receive synaptic inputs, whereas other branches that receive no or only a few

synapses would retract. Such a mechanism could explain the retraction of ectopic dendrites and stabilization of those dendrites that are located within the ‘correct’ sublamina. However, this model assumes that developing RGCs receive more ONthan OFF-type inputs or vice versa even before the onset of stratification. As Wang et al. (2001) point out, this may not necessarily be the case. Furthermore, even if synaptic connectivity is biased before stratification occurs, the question remains what the cues are that help establish this initial bias. Therefore, it is currently not clear whether synaptic activity has an instructive function beyond its permissive role in dendritic remodelling and sublamination of the IPL. Alternatively, differential expression patterns of molecular markers (see p. 256) within the ON and the OFF systems could initiate the segregation of processes into the respective sublaminae.

12.5Concluding remarks

Despite numerous advances in our understanding of how retinal neurons develop and the relationship between form and function in the retina there remain many outstanding issues: patterns of neurite growth that shape receptive fields and create laminated circuitry are uncharacterized for the majority of retinal neuron subtypes. How the relative roles of neuronal activity and molecular guidance are integrated to resolve patterns of circuitry is not understood. Further complicating these issues is the question of whether insights gained from one system can be applied universally or represent evolutionary divergent and/or cell type-specific solutions to a given problem. What roles do specific retinal subtypes play in coordinating arborizations of neighbouring cells and their partners? Elimination of select neuronal subpopulations and/or manipulation of neurotransmission in the retina have been useful in providing some details in this regard; further refinement of these techniques and identification of knockouts or mutants that lack individual neuronal subtypes will provide valuable tools to elaborate further on this question. Beyond determining the roles specific cell types play in regulating connectivity, inducible ablation techniques should allow functional roles to be assigned to targeted neuronal populations at the level of visual behaviours. The ability to link discrete retinal elements – cellular subsets, defined circuits, specific modes of transmission – to specific developmental and/or visual system functions represents perhaps the ultimate goal in the quest to understand how the retina forms and how it functions. The ability to accurately assess changes over time as a series of causally linked events, be they morphological stages or physiological response patterns, is critical to moving this field forward. Fortunately, recent technological advances have provided modern researchers with the means to view the retina from wholly new perspectives (Megason and Fraser, 2003; Morgan et al., 2005, see also Chapters 15 to 17).

Perhaps most notably, with regard to developmental studies, is the advent of highresolution, time-lapse imaging of non-invasive cellular reporters, such as green fluorescent protein (GFP). Transgenesis is being used to express GFP-type reporters in select neuronal subsets in many different model systems. High-resolution microscopy, such as confocal and multiphoton, allows more refined resolution of morphological criteria, such as

sublamination patterns, from these genetically defined subpopulations. From the standpoint of morphological analyses alone retinal neurons can now be visualized, in vivo, from the time of initial neurite outgrowth until fully mature morphologies are resolved. Thus, early neuritic behaviours and nascent morphological stages can be directly linked to final functional forms. Transgenically defined subsets labelled with fluorescent reporters can also be targeted for electrophysiological characterization, an approach historically utilized in the reverse to elucidate the link between sublamination patterning and response patterns. In addition, an ever-expanding palette of fluorescent reporter colours facilitates simultaneous visualization of separate cellular subpopulations, allowing correlations of differentiation state changes and direct interactions between cells to be monitored over time. Thus, multicoloured ‘contextual imaging’ could reveal which specific cell types laminate prior to others, suggesting possible hierarchical orders of dependence, or if partnered populations tend to co-laminate in an interdependent fashion. Fluorescent reporters can also be linked to other proteins in order to reveal discrete subcellular compartments or modified to read out metabolic changes in real time. For instance, reporters that indicate relative levels of neuronal activity and/or that are localized to synapses have been developed. Clearly these and other advances in cellular imaging will provide a wealth of new insights into the formation and function of retinal circuitry in the coming years.

Acknowledgements

We would like to thank Rachel Wong for her mentorship, providing a richly rewarding scientific environment, assistance in the preparation of this manuscript and for all the food; past and present members of the Wong laboratory for valuable insights and discussions; and Josh Morgan for allowing us to abscond and adapt his artistic renderings of the retina. This work was supported by NIH NRSA (JM), DFG (CL), and Schloessmann (CL) fellowships.

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