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  • Review Article
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Vertebrate neural cell-fate determination: Lessons from the retina

Key Points

  • Postmitotic neurons are produced from a pool of cycling progenitors in an orderly fashion during development. It is well established that this process of neural cell-fate determination is regulated by a combination of extrinsic and intrinsic influences.

  • The competence model of retinal development proposes that progenitors pass through a series of competence states. During each state, the progenitors are competent to produce a subset of retinal cell types. A more complex model proposes that a heterogeneous pool of progenitors passes through competence states, with different sub-populations biased to give rise to different subsets of cell types.

  • The available data indicate that competence states are intrinsically determined at the level of gene and protein expression, whereas the production of a particular cell fate from a cell that is within a competence state might be regulated to a large degree by extrinsic signalling.

  • A key question is how a progenitor moves between competence states. Of particular interest is whether there is a need for an active signal or an internal motor to drive a progenitor between competence states, or whether the generation of committed progeny somehow alters the competence of progenitors.

  • Cycling retinal progenitors make several decisions during the cell cycle regarding the fate of their progeny, including the type of cell division they will undergo and the fates of their progeny. A critical question is whether there is a hierarchy of decision-making, whereby cells first decide that both progeny will exit the cell cycle and then use the available extrinsic and intrinsic signalling information to decide on the fate of those cells. Alternatively, cells might make a single, integrated decision. The available data indicate that it is unlikely to be one single decision.

  • Studies of neural cell-fate determination in the cerebral cortex, spinal cord and neural crest have indicated that this model might be applicable to these tissues as well for generating multiple cell types from a progenitor population over time. In all of those tissues, many of the key features of this model have been observed, including changing competence over time and the ability of extrinsic factors acting on progenitors to affect the cell-fate choices of their progeny.

Abstract

Postmitotic neurons are produced from a pool of cycling progenitors in an orderly fashion during development. Studies of cell-fate determination in the vertebrate retina have uncovered several fundamental principles by which this is achieved. Most notably, a model for vertebrate cell-fate determination has been proposed that combines findings on the relative roles of extrinsic and intrinsic regulators in controlling cell-fate choices. At the heart of the model is the proposal that progenitors pass through intrinsically determined competence states, during which they are capable of giving rise to a limited subset of cell types under the influence of extrinsic signals.

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Figure 1: Histology of the adult mammalian retina.
Figure 2: The competence model of retinal cell-fate determination.
Figure 3: Production of postmitotic cells in the neural retina over time.

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References

  1. Cepko, C. L., Austin, C. P., Yang, X., Alexiades, M. & Ezzeddine, D. Cell fate determination in the vertebrate retina. Proc. Natl Acad. Sci. USA 93, 589– 595 (1996).The first proposal of the competence model for retinal development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Edlund, T. & Jessell, T. M. Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system . Cell 96, 211–224 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Harris, W. A. Cellular diversification in the vertebrate retina. Curr. Opin. Genet. Dev. 7, 651–658 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  4. LaVail, M. M., Rapaport, D. H. & Rakic, P. Cytogenesis in the monkey retina. J. Comp. Anat. 309, 86–114 ( 1991).

    CAS  Google Scholar 

  5. Stiemke, M. M. & Hollyfield, J. G. Cell birthdays in Xenopus laevis retina. Differentiation 58, 189 –193 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Young, R. W. Cell differentiation in the retina of the mouse. Anat. Rec. 212, 199–205 (1985).

    Article  CAS  PubMed  Google Scholar 

  7. Carter-Dawson, L. D. & LaVail, M. M. Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine. J. Comp. Neurol. 188, 263–272 (1979).References 4 7 are classic studies that describe the birthdates of the main classes of retinal cells in several species.

    Article  CAS  PubMed  Google Scholar 

  8. Turner, D. L., Snyder, E. Y. & Cepko, C. L. Lineage-independent determination of cell type in the embryonic mouse retina. Neuron 4, 833 –845 (1990).References 8 11 describe the multipotency of retinal progenitors.

    Article  CAS  PubMed  Google Scholar 

  9. Turner, D. L. & Cepko, C. L. A common progenitor for neurons and glia persists in rat retina late in development. Nature 328, 131–136 (1987).

    Article  CAS  PubMed  Google Scholar 

  10. Holt, C. E., Bertsch, T. W., Ellis, H. M. & Harris, W. A. Cellular determination in the Xenopus retina is independent of lineage and birth date. Neuron 1, 15– 26 (1988).

    Article  CAS  PubMed  Google Scholar 

  11. Wetts, R. & Fraser, S. E. Multipotent precursors can give rise to all major cell types of the frog retina. Science 239, 1142–1145 (1988).

    Article  CAS  PubMed  Google Scholar 

  12. Hu, M. & Easter, S. S. Retinal neurogenesis: the formation of the initial central patch of postmitotic cells. Dev. Biol. 207, 309–321 (1999). Describes a hitherto unrecognized order in the genesis of some cell types in a vertebrate retina.

    Article  CAS  PubMed  Google Scholar 

  13. Austin, C. P., Feldman, D. E., Ida, J. A. & Cepko, C. L. Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch. Development 121, 3637–3650 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Belliveau, M. J. & Cepko, C. L. Extrinsic and intrinsic factors control the genesis of amacrine and cone cells in the rat retina. Development 126, 555– 556 (1999).Shows a number of key features of retinal cell-fate determination, including limitations in the competence of retinal progenitors at different times and the ability of extrinsic signals to alter the relative proportions of cell types generated within a given competence state.

    Article  CAS  PubMed  Google Scholar 

  15. Belliveau, M. J., Young, T. L. & Cepko, C. L. Late retinal progenitor cells show intrinsic limitations in the production of cell types and the kinetics of opsin synthesis. J. Neurosci. 20, 2247–2254 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. McConnell, S. K. Fates of visual cortical neurons in the ferret after isochronic and heterochronic transplantation. J. Neurosci. 8, 945– 974 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Briscoe, J. et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded sonic hedgehog signalling. Nature 398, 622–627 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T. M. Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Desai, A. R. & McConnell, S. K. Progressive restriction in fate potential by neural progenitors during cerebral cortical development . Development 127, 2863– 2872 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Selleck, M. A. & Bronner-Fraser, M. The genesis of avian neural crest cells: a classic embryonic induction. Proc. Natl Acad. Sci. USA 93, 9352–9357 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Freeman, M. Cell determination strategies in the Drosophila eye. Development 124, 261–270 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  22. Alexiades, M. R. & Cepko, C. L. Subsets of retinal progenitors display temporally regulated and distinct biases in the fates of their progeny. Development 124, 1119– 1131 (1997).Shows heterogeneity in retinal progenitors and an intrinsic bias in one subset of progenitors to produce distinct cell types.

    Article  CAS  PubMed  Google Scholar 

  23. Lillien, L. & Cepko, C. Control of proliferation in the retina: temporal changes in responsiveness to FGF and TGF-α. Development 115, 253–266 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  24. Lillien, L. Changes in retinal cell fate induced by overexpression of EGF receptor. Nature 377, 158–162 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  25. Dyer, M. A. & Cepko, C. L. Control of Muller glial cell proliferation and activation following retinal injury. Nature Neurosci. 3, 873–880 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Dyer, M. A. & Cepko, C. L. p57Kip2 regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina. Development 127, 3593– 3605 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Ohnuma, S., Philpott, A., Wang, K., Holt, C. E. & Harris, W. A. p27Xic1, a Cdk inhibitor, promotes the determination of glial cells in Xenopus retina. Cell 99, 499–510 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  28. Livesey, F. J., Furukawa, T., Steffen, M. A., Church, G. M. & Cepko, C. L. Microarray analysis of the transcriptional network controlled by the photoreceptor homeobox gene Crx. Curr. Biol. 10, 301–310 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Alexiades, M. R. & Cepko, C. L. Quantitative analysis of proliferation and cell cycle length during development of the rat retina. Dev. Dyn. 205, 293– 307 (1996).Comprehensive study of the kinetics of progenitor proliferation and cell numbers in the developing mammalian retina.

    Article  CAS  PubMed  Google Scholar 

  30. Chenn, A. & McConnell, S. K. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis . Cell 82, 631–641 (1995).Classic study that describes the occurrence of asymmetric progenitor divisions in the mammalian nervous system.

    Article  CAS  PubMed  Google Scholar 

  31. Mione, M. C., Cavanagh, J. F. R., Harris, B. & Parnavelas, J. G. Cell fate specification and symmetrical/asymmetrical divisions in the developing cerebral cortex. J. Neurosci. 17, 2018– 2029 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhong, W., Feder, J. N., Jiang, M. M., Jan, L. Y. & Jan, Y. N. Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron 17, 43–53 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Young, R. W. Cell death during differentiation of the retina in the mouse. J. Comp. Neurol. 229, 362–373 (1984).

    Article  CAS  PubMed  Google Scholar 

  34. Voyvodic, J. T., Burne, J. F. & Raff, M. C. Quantification of normal cell death in the rat retina: Implications for clone composition in cell lineage analysis. Eur. J. Neurosci. 7, 2469–2478 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Jensen, A. M. & Raff, M. C. Continuous observation of multipotential retinal progenitor cells in clonal density culture. Dev. Biol. 188, 267–279 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  36. Reh, T. A. & Tully, T. Regulation of tyrosine hydroxylase-containing amacrine cell number in larval frog retina. Dev. Biol. 114, 463–469 (1986). First report of the possible role of feedback control of progenitor decision-making by postmitotic cells.

    Article  CAS  PubMed  Google Scholar 

  37. Waid, D. K. & McLoon, S. C. Ganglion cells influence the fate of dividing retinal cells in culture. Development 125 , 1059–1066 (1998). Clearly shows feedback inhibition of ganglion cell genesis by postmitotic ganglion cells, and also shows that this action is distinct from the Delta-Notch signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  38. Jasoni, C. L. & Reh, T. A. Temporal and spatial pattern of MASH-1 expression in the developing rat retina demonstrates progenitor cell heterogeneity. J. Comp. Neurol. 369, 319–327 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Brown, N. L. et al. Math5 encodes a murine basic helix-loop-helix transcription factor expressed during early stages of retinal neurogenesis. Development 125, 4821–4833 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Levine, E. M., Close, J., Fero, M., Ostrovsky, A. & Reh, T. A. p27Kip1 regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina. Dev. Biol. 219, 299–314 (2000).

    CAS  PubMed  Google Scholar 

  41. Ezzeddine, Z. D., Yang, X., DeChiara, T., Yancopoulos, G. & Cepko, C. L. Postmitotic cells fated to become rod photoreceptors can be respecified by CNTF treatment of the retina. Development 124, 1055–1067 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  42. Altshuler, D., Lo Turco, J. J., Rush, J. & Cepko, C. Taurine promotes the differentiation of a vertebrate retinal cell type in vitro. Development 119, 1317– 1328 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Levine, E. M., Fuhrmann, S. & Reh, T. A. Soluble factors and the development of rod photoreceptors . Cell. Mol. Life Sci. 57, 224– 234 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770– 776 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Dorsky, R. I., Chang, W. S., Rapaport, D. H. & Harris, W. A. Regulation of neuronal diversity in the Xenopus retina by Delta signalling . Nature 385, 67–70 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Bao, Z. Z. & Cepko, C. L. The expression and function of Notch pathway genes in the developing rat eye. J. Neurosci. 17, 1425–1434 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Furukawa, T., Mukherjee, S., Bao, Z. Z., Morrow, E. M. & Cepko, C. L. rax, Hes1, and notch1 promote the formation of Muller glia by postnatal retinal progenitor cells. Neuron 26, 383–394 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  48. Gaiano, N., Nye, J. S. & Fishell, G. Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26, 395– 404 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Morrison, S. J. et al. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101, 499–510 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  50. Deftos, M. L. & Bevan, M. J. Notch signaling in T cell development . Curr. Opin. Immunol. 12, 166– 172 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Baonza, A. & Garcia-Bellido, A. Notch signaling directly controls cell proliferation in the Drosophila wing disc. Proc. Natl Acad. Sci. USA 97, 2609– 2614 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mathers, P. H., Grinberg, A., Mahon, K. A. & Jamrich, M. The Rx homeobox gene is essential for vertebrate eye development. Nature 387, 603–607 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  53. Hogan, B. L. M., Hirst, E. M. A., Horsburgh, G. & Hetherington, C. M. Small eye(Sey): a mouse model for the genetic analysis of craniofacial abnormalities . Development 103, 115– 119 (1988).

    Article  PubMed  Google Scholar 

  54. Hill, R. E. et al. Mouse small eye results from mutaions in a paired-like homeobox-containing gene. Nature 354, 522–525 (1991).

    Article  CAS  PubMed  Google Scholar 

  55. Belecky-Adams, T. et al. Pax-6, Prox1, and Chx10 homeobox gene expression correlates with phenotypic fate of retinal precursor cells. Invest. Ophthalmol. Vis. Sci. 38, 1293– 1303 (1997).

    CAS  PubMed  Google Scholar 

  56. Chen, C. M. & Cepko, C. L. Expression of Chx10 and Chx10-1 in the developing chicken retina. Mech. Dev. 90, 293–297 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Liu, I. S. et al. Developmental expression of a novel murine homeobox gene ( Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13, 377– 393 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Burmeister, M. et al. Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation . Nature Genetics 12, 376– 384 (1996).Shows dual functions for the transcription factor Chx10 in retinal development: a role in proliferation of progenitors and a second role in differentiation of bipolar cells.

    Article  CAS  PubMed  Google Scholar 

  59. Bennett, G. S., Hollander, B. A. & Laskowska, D. Expression and phosphorylation of the mid-sized neurofilament protein NF-M during chick spinal cord neurogenesis. J. Neurosci. Res. 21, 376–390 ( 1988).

    Article  CAS  PubMed  Google Scholar 

  60. Bennett, G. S. & DiLullo, C. Expression of a neurofilament protein by the precursors of a subpopulation of ventral spinal cord neurons. Dev. Biol. 107, 94– 106 (1985).

    Article  CAS  PubMed  Google Scholar 

  61. Tapscott, S. J., Bennett, G. S. & Holtzer, H. Neuronal precursor cells in the chick neural tube express neurofilament proteins. Nature 292, 836– 838 (1981).

    Article  CAS  PubMed  Google Scholar 

  62. Orkin, S. Diversification of haematopoietic stem cells to specific lineages. Nature Rev. Genet. 1, 57–64 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Xiang, M. et al. The Brn-3 family of POU-domain factors: Primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J. Neurosci. 15, 4762– 4785 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Erkman, L. et al. Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature 381, 603–606 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Furukawa, T., Morrow, E. M. & Cepko, C. L. Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation . Cell 91, 531–541 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Freund, C. L. et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor . Cell 91, 543–553 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Chen, S. et al. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron 19, 1017–1030 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Gan, L., Wang, S. W., Huang, Z. & Klein, W. H. POU domain factor Brn-3b is essential for retinal ganglion cell differentiation and survival but not for initial cell fate specification. Dev. Biol. 210, 469–480 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Gan, L. et al. POU domain factor Brn-3b is required for the development of a large set of retinal ganglion cells. Proc. Natl Acad. Sci. USA 93, 3920–3925 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Waid, D. K. & McLoon, S. C. Immediate differentiation of ganglion cells following mitosis in the developing retina. Neuron 14, 117–124 (1995). This striking study shows that differentiation of ganglion cells can occur within 15 minutes of the exit from M phase. This supports the proposal that there is transcription of genes required in the postmitotic cells before M phase in the progenitor.

    Article  CAS  PubMed  Google Scholar 

  71. Flores, G. V. et al. Combinatorial signaling in the specification of unique cell fates. Cell 103, 75–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Xu, C., Kauffmann, R. C., Zhang, J., Kladny, S. & Carthew, R. W. Overlapping activators and repressors delimit transcriptional response to receptor tyrosine kinase signals in the Drosophila eye. Cell 103, 87– 97 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Halfon, M. S. et al. Ras pathway specificity is determined by the integration of multiple signal-activated and tissue-restricted transcription factors. Cell 103, 63–74 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  74. Qian, X. et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28, 69–80 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  75. Leber, S., Breedlove, S. & Sanes, J. Lineage, arrangement, and death of clonally related motoneurons in the chick spinal cord. J. Neurosci. 10, 2451–2462 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. McConnell, S. K. & Kaznowski, C. E. Cell cycle dependence of laminar determination in developing neocortex. Science 254, 282–285 ( 1991).

    Article  CAS  PubMed  Google Scholar 

  77. Pfaff, S. L., Mendelsohn, M., Stewart, C. L., Edlund, T. & Jessell, T. M. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84, 309–320 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Briscoe, J., Pierani, A., Jessell, T. M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435–445 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Freeman, M. Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87, 651 –660 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. Ikuta, K. et al. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874 (1990).

    Article  CAS  PubMed  Google Scholar 

  81. Weinmaster, G., Roberts, V. & Lemke, G. A homolog of Drosophila Notch expressed during mammalian development. Development 113, 199–205 (1991).

    Article  CAS  PubMed  Google Scholar 

  82. Tomita, K. et al. Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis . Neuron 16, 723–734 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Hitchcock, P. F., Macdonald, R. E., VanDeRyt, J. T. & Wilson, S. W. Antibodies against Pax6 Immunostain amacrine and ganglion cells and neuronal progenitors, but not rod precursors, in the normal and regenerating retina of the gold fish. J. Neurobiol. 29, 399– 413 (1996).

    Article  CAS  PubMed  Google Scholar 

  84. Tomarev, S. I. et al. Chicken homeobox gene Prox1 related to Drosophila prospero is expressed in the developing lens and retina. Dev. Dyn. 206, 354–367 ( 1996); erratum 207, 120 ( 1996). PubMed

    Article  CAS  PubMed  Google Scholar 

  85. Masland, R. H. & Raviola, E. Confronting complexity: strategies for understanding the microcircuitry of the retina. Annu. Rev. Neurosci. 23, 249–284 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. MacNeil, M. A. & Masland, R. H. Extreme diversity among amacrine cells: implications for function. Neuron 20, 971–982 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Ellis, H. M., Spann, D. R. & Posakony, J. W. Extramacrochaetae, a negative regulator of sensory organ development in Drosophila, defines a new class of helix-loop-helix proteins. Cell 61, 27–38 (1990).

    Article  CAS  PubMed  Google Scholar 

  88. Bang, A. G., Bailey, A. M. & Posakony, J. W. Hairless promotes stable commitment to the sensory organ precursor cell fate by negatively regulating the activity of the Notch signaling pathway. Dev. Biol. 172, 479– 494 (1995).

    Article  CAS  PubMed  Google Scholar 

  89. Leviten, M. W. & Posakony, J. W. Gain-of-function alleles of Bearded interfere with alternative cell fate decisions in Drosophila adult sensory organ development. Dev. Biol. 176 , 264–283 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Takahashi, T., Nowakowski, R. S. & Caviness, V. S. Jr The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis . J. Neurosci. 16, 6183– 6196 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lu, B., Jan, L. & Jan, Y. N. Control of cell divisions in the nervous system: symmetry and asymmetry. Annu. Rev. Neurosci. 23, 531–556 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Coffman, C., Harris, W. & Kinter, C. Xotch, the Xenopus homolog of Drosophila Notch. Science 249, 1438– 1441 (1990).

    Article  CAS  PubMed  Google Scholar 

  93. Henrique, D. et al. Maintenance of neuroepithelial progenitor cells by Delta-Notch signalling in the embryonic chick retina. Curr. Biol. 7, 661–670 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Toy, J. & Sundin, O. H. Expression of the optx2 homeobox gene during mouse development. Mech. Dev. 83, 183–186 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Toy, J., Yang, J. M., Leppert, G. S. & Sundin, O. H. The optx2 homeobox gene is expressed in early precursors of the eye and activates retina-specific genes. Proc. Natl Acad. Sci. USA 95, 10643–10648 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Morrow, E. M., Furukawa, T., Lee, J. E. & Cepko, C. L. NeuroD regulates cell fate determination in the developing neural retina. Development 126, 23–36 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  97. Acharya, H. R., Dooley, C. M., Thoreson, W. B. & Ahmad, I. cDNA cloning and expression analysis of NeuroD mRNA in human retina. Biochem. Biophys. Res. Commun. 233, 459– 463 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Yan, R. -T. & Wang, S. -Z. NeuroD induces photoreceptor cell overproduction in vivo and de novo generation in vitro. J. Neurobiol. 36, 485–496 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Matter, J. M., Matter-Sadzinski, L. & Ballivet, M. Activity of the β3 nicotinic receptor promoter is a marker of neuron fate determination during retina development. J. Neurosci. 15, 5919–5928 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the members of the Cepko laboratory for stimulating discussions.

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Correspondence to C. L. Cepko.

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DATABASE LINKS

syntaxin-1a

p27Kip1

Mash1

Math5

p57Kip2

CNTF

LIF

sonic hedgehog

Delta

Notch

Pax6

Rax

Chx10

Brn3

Crx

ENCYCLOPEDIA OF LIFE SCIENCES

Visual system development in vertebrates

Neural development: bHLH genes

Cell cycle: regulation by cyclins

Glossary

CELL FATE

The cell type that a cell will become. This term does not imply commitment or differentiation, only that the cell will eventually become a certain type.

MÜLLER GLIA

The only retinal glia cell that derives from retinal progenitor cells.

PROGENITOR

A mitotic cell that is not capable of indefinite self-renewal and which will produce a limited repertoire of cell types.

MULTIPOTENT

The ability of a cell to take on more than one fate. Lineage analysis has defined retinal progenitor cells to be multipotent. By contrast, other experiments have shown that the cells are limited in their competence to make particular cell types at particular times. So competence is a temporally defined ability that does not show the overall potency of a cell; for example, early retinal progenitor cells cannot respond to late environments by producing late cell types within one to two days, even though their daughters will eventually become late cell types.

BIRTHDATE

The day a progenitor cell undergoes a terminal mitosis that results in production of a postmitotic cell.

COMPETENCE

The ability of a cell to respond to a cue or set of cues to produce a defined outcome.

HETEROCHRONIC

A term usually used in the context of an experiment designed to test the role of the environment from one temporal window on cells from a different one, for example, transplantation of embryonic cells into a postnatal animal, or exposure of postnatal cells to embryonic cells in culture.

VC1.1 EPITOPE

An N-linked carbohydrate that is present in several glycoproteins and proteoglycans.

DIFFERENTIATION

The elaboration of particular characteristics expressed by an end-stage cell type, or by a cell en route to becoming an end-stage cell. This term is not synonymous with commitment, but differentiation features are used to determine when a cell is committed.

HELIX-LOOP-HELIX

A structural motif present in many transcription factors, which is characterized by two α-helices separated by a loop.

SPECIFICATION

A cell that is competent to make a particular cell type might begin to differentiate along the pathway to become that cell type, but it might not be committed to that fate, that is, its differentiation can be reversed and another fate can be achieved through respecification.

HOMEOBOX

A sequence of about 180 base pairs that encodes a DNA-binding protein sequence known as the homeodomain.

COMMITMENT

An irreversible decision to produce or become a particular cell type. This is defined operationally as the refusal of a cell to change its fate when exposed to various different environments.

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Livesey, F., Cepko, C. Vertebrate neural cell-fate determination: Lessons from the retina. Nat Rev Neurosci 2, 109–118 (2001). https://doi.org/10.1038/35053522

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