The role of tangential dispersion in retinal mosaic formation
Introduction
The architectural complexity of the retina is brought about by various developmental events including proliferation, fate determination, migration, process outgrowth, target cell recognition, synaptogenesis and cell death. These events gradually establish a precisely layered structure in which distinct types of retinal neuron become situated in three cellular layers, interconnected by two intervening synaptic layers. Within this layered architecture, certain cell types are distributed in orderly arrays across a given layer so that they ensure a uniform sampling of the retinal surface. These orderly arrays, or “mosaics”, of retinal nerve cells are a prime example of pattern formation during development, but the developmental mechanism responsible for the establishment of this patterning remains to be defined. Indeed, multiple developmental processes may contribute to the assembly of such orderly distributions of nerve cells (Wässle and Riemann, 1978; Cook and Chalupa, 2000).
This regularity in the cellular spacing of retinal mosaics has often been interpreted as being due to the action of lateral inductive and inhibitory events that determine cellular fate. The precisely organized and repeating nature of cellular positioning within the eye of Drosophila, produced by cellular interactions governing fate determination (Lawrence, 1992; Wolff et al., 1997), has been regarded as a model for understanding vertebrate retinal mosaic formation (Wikler and Rakic (1991), Wikler and Rakic (1994)), and recent studies have begun to identify homologous molecular determinants of cell fate in the vertebrate retina (Dorsky et al (1995), Dorsky et al (1997)). Indeed, a myriad of recent studies have revealed multiple ligand–receptor interactions during vertebrate retinal development that influence cellular fate (Lillien, 1995; Ezzeddine et al., 1997; Lillien and Wancio, 1998; McFarlane et al., 1998; Dyer and Cepko, 2001). These studies are consistent with a model in which the competence of multipotent progenitors varies in the presence of an increasingly heterogeneous microenvironment to generate retinal neurons and glia in reproducible ratios across the retinal surface (Cepko et al., 1996; Jasoni and Reh, 1996; Alexiades and Cepko, 1997), with later generated cell types spacing out those produced earlier in development (Harman and Beazley, 1989; Wikler and Rakic, 1994). Subtle alterations in these interactions have been proposed to account for species-typical variations upon a vertebrate theme, producing, for example, the changing ratio of ganglion cells to other retinal neurons across eccentricity in primates, or the characteristic differences in the retinas of nocturnal versus diurnal rodents (Harman and Beazley, 1989; Reichenbach et al., 1998). If such fate-determining events occur periodically across the developing retina, as has been shown at the leading edge of retinal proliferation (e.g: McCabe et al., 1999), this may be sufficient to establish the periodicity in retinal mosaics observed in maturity (Fig. 1).
Consistent with this view is the widespread assumption that retinal neurons become postmitotic at a particular locus on the retinal surface and subsequently move only radially to occupy an appropriate depth in the retina for a given cell type (Luskin, 1994), preserving their relative positioning at the time of fate determination. By contrast with the phenomenal distances migrated by cortical neuroblasts, employing radial glial guides in their migration out of a germinal zone to form the cortical plate (Rakic, 1972; Gadisseux et al., 1990; Fishell and Hatten, 1991; Zheng et al., 1996), newborn retinal neurons move only modest distances, or not at all, and the germinal zone is progressively transformed into the mature retinal structure (Sidman, 1961; Zimmerman et al., 1988; Polley et al., 1989). The use of lineage tracing techniques to study clonal relationships provided the first clear evidence for this presumption, when individual retinal progenitors were either labelled with heritable cytoplasmic markers or were transfected with replication-deficient retroviruses encoding reporter genes (Turner and Cepko, 1987; Holt et al., 1988; Wetts and Fraser, 1988; Turner et al., 1990), and similar results were subsequently reported for chimeric mice in which highly imbalanced chimeras revealed the distribution of presumed clones (Williams and Goldowitz, 1992). These studies all reported that, not only were progenitor cells multipotent, but that their progeny were distributed as precise radial columns within the retina. The implication of the latter observation was that these cells, upon their birth, must move exclusively in the radial axis. This too was in contrast with experimental observations in the developing neocortex, in which siblings in a clone become dispersed by the time they arrive within the cortical plate (Walsh and Cepko, 1993; O’Rourke et al., 1995; Reid et al., 1997; Tan et al., 1998).
Those same retinal lineage studies occasionally detected individual clonally related cells that were separated from the clonal column by a few cell diameters. These individual cells were often interpreted as being either artifactual or ectopic; the fact that they were extremely rare led them to be ignored or dismissed (Turner and Cepko, 1987; Holt et al., 1988; Wetts and Fraser, 1988; Turner et al., 1990; Williams and Goldowitz, 1992). Subsequent interpretations of their organizational insignificance were that they became displaced from their clonal columns by passive forces generated during retinal expansion (Goldowitz et al., 1996), or that they were produced as a consequence of their mitotic sibling moving laterally within the germinal zone before continuing proliferation of the remaining clonal column (Fekete et al., 1994), analogous to the movements of dividing cells detected within the telencephalic germinal zone (Fishell et al., 1993). In fact, we now know that tangential dispersion is a universal feature of certain cell types within the retina, occurring amongst all members of a given type. The significance of this lateral displacement is that it may reflect an active movement of the postmitotic cell in the presence of cell–cell interactions which ultimately contributes to the regularity within a retinal mosaic, an hypothesis originally proposed by Wässle and Riemann (1978) but which has received relatively little support over the years. The present review considers the evidence for this perspective.
The key experimental observation for this hypothesis came from studies using X-inactivation mosaic mice (Tan et al., 1993), in which the lacZ reporter transgene, under the control of a promoter for a ubiquitous housekeeping gene (Gautier et al., 1989), had been serendipitously integrated on the X-chromosome (Tan et al., 1995). Because of the natural and random phenomenon of X-inactivation, the transgene is switched off in ≈50% of all retinal progenitors in female hemizygous mice, and the clonal descendents of these cells inherit the X-active status of their ancestor at the time of X-inactivation (Fig. 2). Since X-inactivation occurs prior to the onset of retinal neurogenesis, the benefit of this approach is that it enables the marking of roughly half of all retinal clones. In the adult retina, the organization of most of the cells in these clones is precisely columnar (Fig. 3a), as might have been expected from the above lineage-tracing studies. Surprisingly however, certain cell types are often observed to be displaced laterally with respect to their clonal columns of origin. These cell types include the cone, horizontal, amacrine and ganglion cells (Reese et al., 1995). As these cell types are composed of subclasses that are known to be assembled into orderly mosaics, their tangential dispersion may contribute to the assembly of this mosaic order. The following discussion in this section will address a number of aspects associated with these tangentially dispersing neurons: How common is this phenomenon of tangential dispersion? How far do retinal neurons disperse tangentially? When does tangential dispersion occur? And what is its relationship to morphological differentiation? The subsequent section will then consider its consequences for the establishment of the mature retinal architecture: Ultimately, might it play a role in the formation of orderly retinal mosaics?
Section snippets
Tangential dispersion of retinal neuroblasts
The use of these X-inactivation transgenic mice has been key to recognizing the frequency of tangential dispersion within individual cell types, because 50% of the progenitor population is labelled, and because the labelling is established before any retinal neurons had become post-mitotic (i.e: X-inactivation occurs around E−8.5, Tan et al., 1993). These two features overcome problems associated with other single-cell lineage-tracing approaches. First, those approaches have been generally less
The formation of retinal mosaics
Do these experimental results documenting tangential dispersion and its developmental time-course have anything to do with retinal mosaic formation? Understanding the formation of retinal mosaics has been hindered by the fact that most markers of retinal cells that display orderly arrays in adulthood are not expressed during the period of mosaic formation (but see Wikler and Rakic, 1994; Raymond et al., 1995, for exceptions amongst the photoreceptor populations). It has recently been
Future directions
The nature of the homotypic cell–cell interactions in relation to the differentiation of tangentially oriented processes remains to be determined. The adult morphology of a cell is certainly no indication of whether that cell type will disperse tangentially, and nor is density. The cholinergic amacrine cells and the horizontal cells in the mouse retina are similarly dense and comparably regular, yet their mature morphologies and dendritic overlap are conspicuously different. Imaging the
Acknowledgements
This research program was supported by the NIH (EY-11087), the CNR and the Telethon Foundation.
References (75)
- et al.
An investigation into the role of ganglion cells in the regulation of division and death of other retinal cells
Dev. Brain Res.
(1987) - et al.
Retinal mosaicsnew insights into an old concept
Trends Neurosci.
(2000) - et al.
Xotch inhibits cell differentiation in the Xenopus retina
Neuron
(1995) - et al.
Clonal analysis in the chicken retina reveals tangential dispersion of clonally related cells
Dev. Biol.
(1994) - et al.
Neuron migration within the radial glial fiber system of the developing murine cerebruman electron microscopic autoradiographic analysis
Dev. Brain Res.
(1990) - et al.
Clonal architecture of the mouse retina
Prog. Brain Res.
(1996) - et al.
Generation of retinal cells in the wallaby, Setonix brachyurus (Quokka)
Neuroscience
(1989) - et al.
Early ganglion cell differentiation in the mouse retinaan electron microscopic analysis utilizing serial sections
Dev. Biol.
(1974) - et al.
Cellular determination in the xenopus retina is independent of lineage and birth date
Neuron
(1988) - et al.
Changes in epidermal growth factor receptor expression and competence to generate glia regulate timing and choice of differentiation in the retina
Mol. Cell. Neurosci.
(1998)
The development of astrocytes in the cat retinaevidence of migration from the optic nerve
Dev. Brain Res.
Ontogeny of the primate foveaa central issue in retinal development
Prog. Neurobiol.
Neurogenesis in the retinal ganglion cell layer of the rat
Neuroscience
Clonal boundary analysis in the developing retina using X-inactivation transgenic mosaic mice
Sem. Cell Dev. Biol.
Separate progenitors for radial and tangential cell dispersion during development of the cerebral neocortex
Neuron
Lineage-independent determination of cell type in the embryonic mouse retina
Neuron
Irregular S-cone mosaics in felid retinas. Spatial interaction with axonless horizontal cells, revealed by cross-correlation
J. Opt. Soc. Am., A
Subsets of retinal progenitors display temporally regulated and distinct biases in the fates of their progeny
Development
Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine
J. Comp. Neurol.
Retinal ganglion cells with NADPH-diaphorase activity in the chick form a regular mosaic with a strong dorsoventral asymmetry that can be modelled by a minimal spacing rule
Eur. J. Neurosci.
Cell fate determination in the vertebrate retina
Proc. Natl. Acad. Sci.
Getting to grips with neuronal diversitywhat is a neuronal type?
Regulation of neuronal diversity in the Xenopus retina by Delta signalling
Nature
Birth dates of retinal ganglion cells giving rise to the crossed and uncrossed optic projections in the mouse
Proc. R. Soc., London
p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations
J. Neurosci.
Lateral cell movement driven by dendritic interactions is sufficient to form retinal mosaics
Network: Comput. Neural Syst.
Postmitotic cells fated to become rod photoreceptors can be respecified by CNTF treatment of the retina
Development
Astrotactin provides a receptor system for CNS neuronal migration
Development
Dispersion of neural progenitors within the germinal zones of the forebrain
Nature
Local, possibly contact-mediated signalling restricted to homotypic neurons controls the regular spacing of cells within the cholinergic arrays in the developing rodent retina
Development
Mosaics of islet-1 expressing amacrine cells assembled by short range cellular interactions
J. Neurosci.
Modelling the mosaic organization of rod and cone photoreceptors with a minimal-spacing rule
Eur. J. Neurosci.
A ubiquitous mammalian expression vector, pHMG, based on a housekeeping gene promoter
Nucleic Acids Res.
Primate foveal developmentA microcosm of current questions in neurobiology
Invest. Ophthalmol. Visual Sci.
Differentiation of photoreceptors and horizontal cells in the embryonic mouse retinaan electron microscopic, serial section analysis
J. Comp. Neurol.
Development of retinal amacrine cells in the mouse embryoevidence for two modes of formation
J. Comp. Neurol.
Cited by (64)
1.19 - Retinal Mosaics
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second EditionMetabolic profiling of the mouse retina using amino acid signatures: Insight into developmental cell dispersion patterns
2013, Experimental NeurologyCitation Excerpt :Previous analysis of cell dispersion patterns indicates that two distinct migration patterns co-operate to form the retinal mosaic during retinogenesis (Rapaport et al., 2004; Reese and Tan, 1998; Reese et al., 1995, 1999). Rod photoreceptors, Müller cells and bipolar cells participate in radial dispersion whereas cone photoreceptors, horizontal cells, amacrine cells and ganglion cells exhibit radial and tangential dispersions (Reese and Galli-Resta, 2002). Macromolecular markers have distinguished the identity of some radially migrating cell populations such as dopaminergic amacrine cells and other tangentially dispersed populations such as cholinergic amacrine cells (Acosta et al., 2008; Eglen et al., 2003; Galli-Resta et al., 1997, 2000; Raven and Reese, 2002; Reese et al., 1999).
Assembly and disassembly of a retinal cholinergic network
2012, Visual NeuroscienceChromatic organization of retinal photoreceptors during eye migration of Atlantic halibut (Hippoglossus hippoglossus)
2023, Journal of Comparative Neurology