Trends in Neurosciences
ReviewLineage in the vertebrate retina
Section snippets
Are retinal lineages programmed?
The retina is a layered structure (Figure 1), and the cell bodies of the rods and cones are located in the outer nuclear layer. Horizontal cells, bipolar cells, Müller cells and amacrine cells reside in the inner nuclear layer of the retina, and retinal ganglion cells (RGCs) are in the innermost layer. Birth-dating studies of the retinas of various vertebrate species agree that there is temporal order to the genesis of these cell types 1, 2, 3 (Figure 2). In all vertebrates, RGCs, horizontal
Intrinsic clocks
The relationship between lineage and histogenesis is certainly consistent with the idea of a developmental clock. The intrinsic nature of such a clock in the retina was first suggested by the fact that progenitors cultured in vitro do not start to express the rod photoreceptor marker opsin until they reach the age at which they normally express it in vivo, even when they are mixed with an excess of older cells that have already begun to express opsin [13]. Combined with similar results reported
Intrinsic factors influence lineage potential
Recent studies of isolated cortical progenitors show that these cells divide to generate neurons in their normal ‘inside-out’ histogenetic order [18]. Moreover, once cortical progenitors begin to generate neurons typical of a particular layer, they are prevented from generating earlier-born neurons. Isolated late retinal progenitors, cultured at clonal density, are also able to give rise to clones of the same general birth order, size and composition as clones in vivo [12]. The presence of a
Tying intrinsic determinants to the cell cycle
An important question for understanding histogenesis is how cell cycle exit is coordinated with cellular determination. During the cell cycle, the nuclei of vertebrate neuroepithelial cells go through M phase at the apical or ventricular surface, then migrate during G1 towards the basal surface where they go through S phase, and journey back to the apical surface again during G2. When neuroepithelial cell nuclei are situated basally, and so in or near S phase, they express Notch1, Delta1 and
Influence of environmental signals on cell lineage
We have, until this point in the review, spoken mainly of intrinsic influences in lineage, but we should remember that the early studies of lineage in the retina suggested that extrinsic factors would provide the most parsimonious explanation for the variety of clonal compositions seen in vivo [37]. Moreover, such mechanisms have plausibility because as retinal development proceeds the environment changes, simply as a result of various retinal cell types being generated. Signals secreted by
What are the environmental signals and how do they work?
What might these feedback signals be? RGCs express sonic hedgehog (Shh), and Shh knockout mice contain increased number of RGCs [43]. These results suggest that Shh provides a feedback inhibition signal in the developing mouse retina. Growth differentiation factor 11 (GDF11) is also expressed in RGCs and seems to act by limiting the temporal window during which progenitors are competent to express ath5 and thus produce RGCs [44]. Signals such as Shh and GDF11, and the fibroblast growth factors
Oriented and asymmetric cell divisions in retinal lineages
The formation of a cell lineage involves multiple rounds of cell division, some of which will be symmetric and some of which will be asymmetric (Box 1). Increasing evidence now suggests that the production of different combinations of daughter cell pairs involves the regulation of the orientation of cell division. By controlling the orientation of cell division, progenitor cells can distribute cell-fate determinants to one or both daughter cells, thereby producing symmetric or asymmetric
Concluding remarks
In the developing retina, multipotent progenitor cells generate the variety of mature retinal cell types. Although some earlier studies suggested a potential role for cell lineage in retinal cell-fate decisions 64, 65, 66, 67, the apparent randomness in the cellular composition of clones suggested that fate decisions in the retina might be largely independent of lineage. Recent results suggest that lineage programs are more important than previously believed, but that retinal lineages can also
Acknowledgements
We would like to thank the Canadian Institutes of Health Research (M.C.) and the Wellcome Trust (W.A.H), who supported this work. M.C. is a Canadian Institutes of Health Research New Investigator and a W.K. Stell Scholar of the Foundation Fighting Blindness – Canada.
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