Trends in Neurosciences
Volume 29, Issue 10, October 2006, Pages 563-570
Journal home page for Trends in Neurosciences

Review
Lineage in the vertebrate retina

https://doi.org/10.1016/j.tins.2006.08.003Get rights and content

Recent results are changing the way we think about cell-fate decision mechanisms in the retina. For a long time it was accepted that lineage was not important in retinal cellular determination but, as we review here, new data show that lineage programmes might be at the heart of this process. These programmes are intrinsic, but they are also plastic and are influenced by extrinsic signals.

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.

References (73)

  • Z. Yang

    Math5 determines the competence state of retinal ganglion cell progenitors

    Dev. Biol.

    (2003)
  • X. Mu

    A gene network downstream of transcription factor Math5 regulates retinal progenitor cell competence and ganglion cell fate

    Dev. Biol.

    (2005)
  • A. Murciano

    Interkinetic nuclear movement may provide spatial clues to the regulation of neurogenesis

    Mol. Cell. Neurosci.

    (2002)
  • S. Ohnuma

    p27Xic1, a Cdk inhibitor, promotes the determination of glial cells in Xenopus retina

    Cell

    (1999)
  • C.L. Cepko

    The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates

    Curr. Opin. Neurobiol.

    (1999)
  • T.A. Reh et al.

    Regulation of tyrosine hydroxylase-containing amacrine cell number in larval frog retina

    Dev. Biol.

    (1986)
  • D.K. Waid et al.

    Immediate differentiation of ganglion cells following mitosis in the developing retina

    Neuron

    (1995)
  • X. Mu

    Ganglion cells are required for normal progenitor-cell proliferation but not cell-fate determination or patterning in the developing mouse retina

    Curr. Biol.

    (2005)
  • T. Furukawa

    rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells

    Neuron

    (2000)
  • M.L. Schneider

    Notch signaling can inhibit Xath5 function in the neural plate and developing retina

    Mol. Cell. Neurosci.

    (2001)
  • D. Henrique

    Maintenance of neuroepithelial progenitor cells by Delta–Notch signalling in the embryonic chick retina

    Curr. Biol.

    (1997)
  • T. Das

    In vivo time-lapse imaging of cell divisions during neurogenesis in the developing zebrafish retina

    Neuron

    (2003)
  • K. Sanada et al.

    G protein βγ subunits and AGS3 control spindle orientation and asymmetric cell fate of cerebral cortical progenitors

    Cell

    (2005)
  • Y. Sun

    Asymmetric distribution of EGFR receptor during mitosis generates diverse CNS progenitor cells

    Neuron

    (2005)
  • W.B. Huttner et al.

    Asymmetric division and polarity of neuroepithelial cells

    Curr. Opin. Neurobiol.

    (1997)
  • W.B. Huttner et al.

    Symmetric versus asymmetric cell division during neurogenesis in the developing vertebrate central nervous system

    Curr. Opin. Cell Biol.

    (2005)
  • M. Zigman

    Mammalian inscuteable regulates spindle orientation and cell fate in the developing retina

    Neuron

    (2005)
  • R.W. Williams et al.

    Lineage versus environment in embryonic retina: a revisionist perspective

    Trends Neurosci.

    (1992)
  • X. Qian

    Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells

    Neuron

    (2000)
  • M. Schaefer

    A protein complex containing inscuteable and the Gα-binding protein Pins orients asymmetric cell divisions in Drosophila

    Curr. Biol.

    (2000)
  • F. Yu

    Analysis of partner of inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in inscuteable apical localization

    Cell

    (2000)
  • J. Betschinger et al.

    Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates

    Curr. Biol.

    (2004)
  • C.L. Cepko

    Cell fate determination in the vertebrate retina

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • D.H. Rapaport

    Timing and topography of cell genesis in the rat retina

    J. Comp. Neurol.

    (2004)
  • R. Sidman

    Histogenesis of the mouse retina studied with tritiated thymidine

  • J. Price

    Lineage analysis in the vertebrate nervous system by retrovirus-mediated gene transfer

    Proc. Natl. Acad. Sci. U. S. A.

    (1987)
  • Cited by (0)

    View full text