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

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ILM

(d)

OLM

Figure 4.1 Proposed migratory modes for a retinal cell. (a) Guided migration: having left the cell cycle at the OLM a postmitotic retinal cell (black) might use a cellular substrate (grey) as a scaffold to migrate upon until it reaches a depth in the retina appropriate for its phenotype. The identity of the cellular substrate as M¨uller glial cells remains contentious. Cycling neuroepithelial cells, with cytoplasmic processes spanning the depth of the retina from the OLM to the ILM might be suitable

for the INL and ONL. This is followed by the generation of bipolar cells and M¨uller glial cells. Rod photoreceptor cells are generated over an extended developmental time, overlapping with the periods of cytogenesis of most other cell types (Sidman, 1961; CarterDawson and LaVail, 1979; Young, 1985a,b).

How do retinal cells that are generated concurrently migrate appropriately to different layers? Clues about the cellular mechanisms newborn retinal cells use to migrate to their definitive positions come largely from morphological observations at progressive stages of development. In addition, gene expression and genetic studies are beginning to shed light on the molecular machinery that directs cell migration and positioning in the retina.

4.2 Cellular mechanisms of migration

Drawing from static observations in the retina and from studies of migration in the neocortex, the CNS structure morphologically most analogous to the retina, three cellular mechanisms have been proposed to account for the way in which newborn retinal cells migrate to their final positions: glial-guided migration, somal translocation and unconstrained migration.

4.2.1Glial-guided migration

Postmitotic retinal neurons have been suggested to migrate to their definitive positions along M¨uller glial cells. Like radial glial cells that span the thickness of the neocortex and have been shown to mediate neuronal migration, M¨uller glial cells span the retinal neuroepithelium and have therefore been regarded as good candidates to provide a scaffold for retinal cell migration (Meller and Tetzlaff, 1976; Wolburg et al., 1991) (Figure 4.1a). Radial glial cells are present at the earliest time-points of cortical development; their somata lie in the ventricular zone and their processes span the entire thickness of the developing cerebral wall. Thus, temporally and spatially, radial glial cells are good candidates for a guidance role. In addition, electron microscopy studies suggest a close apposition between postmitotic neurons and radial glial fibres (Rakic, 1972; Gadisseux et al., 1990; Misson et al., 1991) and observations of this apposition both in vivo (Miyata et al., 2001; Noctor

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Figure 4.1 (cont.) candidates for such a role. (b) Somal translocation: in this mode of migration, a retinal cell might extend a cytoplasmic process basally until it reaches the ILM. It then translocates its cell body within this process until it reaches the appropriate lamina, while still being anchored at the OLM. Upon arriving at its destination, the cell would retract its apically and basally directed processes. (c) Unconstrained migration: with no attachments to the apical or basal surfaces, cells may migrate to their proper position using their neurites to explore the environment along the way. (d) Retinal cell exhibiting unconstrained migration in zebrafish retina. A presumed postmitotic retinal cell (arrow) labelled using an α-tubulin promoter driving green fluorescent protein (GFP) was followed by time-lapse confocal microscopy in vivo. With no cytoplasmic attachments to either the OLM or ILM, the cell moved vitreally, extending highly motile neurites as it did so. The GFP-labelled cell to the right appeared to lose its cytoplasmic attachment to the ILM (140’, 250’) while maintaining an attachment to the OLM. (L. Godinho and J. S. Mumm, unpublished images.)

et al., 2001) and in vitro (Edmondson and Hatten, 1987; O’Rourke et al., 1992; Anton et al., 1996) lend strong support for radial glial-guided migration. Time-lapse observations of DiI-labelled cortical neurons in slice cultures undergoing glial-guided migration revealed cells with short leading and trailing cytoplasmic processes displaying saltatory movement (Edmondson and Hatten, 1987; Nadarajah et al., 2001).

Birthdating studies suggest that M¨uller cells are generated late during the period of cell genesis, after many other retinal cells, including amacrine and ganglion cells, have already migrated to their appropriate layer. It therefore seems unlikely that M¨uller cells provide a guidance role, at least at the earliest time-points in development. Immunoreactivity for vimentin, a glia-specific antigen, and electron-microscopic observations were both used to suggest that radial glial cells are present in the immature retina, earlier than suggested by birthdating studies (Meller and Tetzlaff, 1976; Wolburg et al., 1991). However, vimentin may not be a specific marker for glial cells early in development and electron microscopy may not indisputably identify glial cells (Lemmon and Rieser, 1983; Bennett and DiLullo, 1985). As an alternative to M¨uller glia, mitotically active neuroepithelial cells, with their cytoplasmic processes contacting both ends of the epithelium, have also been proposed as candidates to act as guide posts for migrating cells (Malicki, 2004) (Figure 4.1a). However, evidence in support of a direct role for both M¨uller glia or cycling neuroepithelial cells in mediating migration is lacking.

4.2.2 Somal translocation

Translocation of their somata is another means by which retinal cells have been proposed to migrate to the appropriate laminar position (Morest, 1970; Snow and Robson, 1994, 1995). In this scenario, a newly postmitotic cell at the apical surface extends a cytoplasmic process towards the ILM, while maintaining contact with the OLM. The cell body then translocates within this process, until it reaches a position in the depth of the retina appropriate for its phenotype after which it retracts its cytoplasmic extensions from both the apical and basal sides of the neuroepithelium (Figure 4.1b). Evidence for this mode of migration in the retina comes from studies of the morphology of retinal neuroblasts by Golgi impregnations (Morest, 1970; Prada et al., 1981). Somal translocation is further supported by observations of ganglion cell morphology at progressive developmental stages. Taking advantage of the fact that ganglion cells extend an axon soon after becoming postmitotic, several studies used applications of the carbocyanine dye DiI (Snow and Robson, 1994, 1995) or horseradish peroxidase (Dunlop, 1990) onto the optic nerve to retrogradely label these cells. At early developmental ages ganglion cells with a bipolar morphology were found. Cell bodies were found at various depths within the developing neuroepithelium, with an axon extending toward the ILM and a cytoplasmic process attached to the apical surface. Apically directed cytoplasmic processes persisted even when ganglion cell somata reached their prospective final destination in the inner retina. However, these processes were subsequently lost when dendritic growth was initiated. Similar observations were made when ganglion cell-specific

antibodies (McLoon and Barnes, 1989) and other immunohistochemical markers (Brittis et al., 1995) were used to label ganglion cells during development.

The first hints of somal translocation in the cortex came from morphological observations during development (Morest, 1970; Brittis et al., 1995). Time-lapse experiments in mouse embryonic brain slices permitted a direct observation of this migratory mode (Nadarajah et al., 2001). Cortical cells undergoing somal translocation have a process extending to the pial surface while still maintaining an attachment in the ventricular zone. As the nucleus moves through the cytoplasm towards the pia, the leading process shortens and the apical cytoplasmic attachment to the ventricular surface is gradually lost. Compared with cells engaged in glial-guided migration, the movement of translocating cells in the cortex was found to be continuous towards the pial surface and at greater average speeds (Nadarajah et al., 2001).

4.2.3 Unconstrained migration

Both translocating cells and cells using substrates as guides to migrate upon are restricted in their migratory path. In contrast to this, some retinal cells are believed to engage in what has been called ‘free’ migration (Prada et al., 1987). Following exit from the mitotic cycle, these cells are thought to simply travel to their definitive layer without the aid of cytoplasmic anchors at the OLM and ILM (Figure 4.1c). The first suggestions of this unconstrained migration came from electron microscopy studies that described ganglion, amacrine and horizontal cell precursors, each bearing morphological hallmarks of freely migrating cells (Hinds and Hinds, 1978, 1979, 1983). Golgi impregnations of amacrine cell neuroblasts also hinted at free migration (Prada et al., 1987). In this study, two morphologically distinct amacrine cell neuroblasts were described: first, a bipolar-shaped cell type with short processes directed sclerally and vitreally and second, a multipolar cell type with multiple shorter cytoplasmic processes. As development progressed, both cell types were found at locations closer to their prospective destination within the INL (Prada et al., 1987). Recent advances in the ability to transgenically label cells in the zebrafish retina have permitted the direct observation of freely migrating cells in the zebrafish retina in vivo (Figure 4.1d). With a lack of anchorage to either limiting membrane, it is likely that such migrating cells move through the retinal neuroepithelium interacting with other cells as well as the extracellular matrix (ECM). The morphological features of freely migrating cells suggest an ability to explore the environment through their neurites. Such explorations would allow for the detection of migratory cues.

In the cortex, unconstrained migratory cells have been observed in acute slice preparations (Nadarajah et al., 2003; Tabata and Nakajima, 2003). These cells are characterized by abundant, highly motile cytoplasmic processes and consequently were referred to as ‘multipolar’ (Tabata and Nakajima, 2003) or ‘branching’ (Nadarajah et al., 2003). Interestingly, such multipolar cells were also found to display an ability to move laterally. These cells were not found closely apposed to radial glial fibres or to tangentially oriented axon