endowed upon a cell by expression of a combination of transcription factors. These factors may direct synthesis of surface receptors or elements in signal transduction cascades so that a cell can respond to a particular set of cues. In addition, the transcription factors respond directly and/or direct the response to signal transduction cascades in order for differentiation to begin. A state of competence is transient. It appears that when a cell moves from one state to the next, it cannot go back to a previous state, as discussed above concerning the competence of chicken retinal cells to make ganglion cells (Fig. 3 and ref.37), as suggested by other experiments carried out in vitro (20,50), and by transplantation in vivo (D. Fekete and C.L.C., unpublished results). Commitment is achieved when extrinsic factors allow stabilization of the network of transcription factors and/or lead to production of a stable group of factors so that the cell is no longer dependent upon environmental cues to move forward in a program of differentiation. The transition from one state of competence to the next may be due to extrinsic cues or an intrinsic program.
The above hypothesis concerns specific signals between a competent cell and its environment. Over the past few years, as many specific receptors and ligands have been identified, it has been noted that signaling through these receptors triggers relatively few signal transduction cascades. For example, the ras cascade is triggered by most receptor tyrosine kinases (36,51,52), and phosphorylation of the STAT family of transcription factors occurs as a result of signaling through the cytokine receptors ( 35). In addition to the apparent convergence of many specific signals into these pathways, disparate cell types have another common signal transduction pathway that is critical to differentiation. Signaling through the Notch/glp/lin receptor family has been shown to regulate differentiation in many types of cells in both invertebrates and vertebrates (39). Finally, a recently described barrier to differentiation, repression by the transcription factor, yan, has been hypothesized to control differentiation in many types of Drosophila cells (53,54). As yan is downstream of ras and is a target of the mitogen-activated protein kinase, a need to reduce yan activity could explain the fact that differentiation of many cell types involves stimulation of the ras/mitogen-activated protein kinase pathway (36,51,52). Although a vertebrate homologue of yan has not been identified, yan is an ETS domain transcription factor, and since a number of ETS domain transcription factors have been found in vertebrate genomes (55), a yan homologue will most likely be found.
How does stimulation of a few common pathways lead to the generation of so many types of cells? The developmental history of each cell, which contributes to its state of competence, has to be critical in the choice of cell fate. There must be a selection within the cell of which genes will respond to the signal transduction cascades. Such genes are just beginning to be identified—for example, phyllopod in the Drosophila eye (56,57). In addition, some of the genes that contribute to competence and/or control the response to extracellular cues have been identified, such as the homeodomain gene, rough (58,59), also in the Drosophila eye. Given the fairly limited number of signal transduction cascades identified to date, the contribution of the developmental history and competence to the generation of diversity cannot be overstated.
We thank David Cardozo, Eric Morrow, Michael Belliveau, Zhengzheng Bao, David Feldheim, and Jeff Golden for helpful comments on the manuscript and the past and present members of the Cepko Laboratory for stimulating discussions concerning the ideas and data discussed herein. The authors also gratefully acknowledge the help of Michael Belliveau in the preparation of the figures.
1. Marti, E., Bumcrot, D. A., Takada, R. & McMahon, A. P. ( 1995) Nature (London) 375, 322–324.
2. Roelink, H., Porter, J. A., Chiang, C., Tanabe, Y., Chang, D. T., Beachy, P. A. & Jessell, T. M. ( 1995) Cell 81, 445–455.
3. Hynes, M., Porter, J. A., Chiang, C., Chang, D., Tessier-Lavigne, M., Beachy, P. A. & Rosenthal, A. ( 1995) Neuron 15, 35–44.
4. Slack, J. M. W. ( 1991) From Egg to Embryo (Cambridge Univ. Press, Cambridge, MA), 2nd Ed.
5. Mintz, B. ( 1970) Symp. Int. Soc. Cell Biol. 9, 15.
6. Dowling, J. E. ( 1987) The Retina—An Approachable Part of the Brain (Harvard Univ. Press, Cambridge, MA).
7. Mann, I. ( 1928) Trans. Ophthal. Soc. U.K. 47, 172.
8. Young, R. W. ( 1985) Dev. Brain Res. 21, 229–239.
9. Drager, U. C. & Olsen, J. F. ( 1980) J. Comp. Neurol. 191, 383–412.
10. Young, R. W. ( 1984) J. Comp. Neurol. 229, 362–373.
11. Young, R. W. ( 1985) Anat. Rec. 212, 199–205.
12. Altshuler, D., Turner, D. & Cepko, C. ( 1991) Development of the Visual System, Proceedings of the Retina Research Foundation Symposia (Massachusetts Inst. of Technology, Cambridge, MA), 37–58.
13. Cagan, R. ( 1993) Development (Cambridge, U.K.) Supplement, 19–28.
14. Tomlinson, A. & Ready, D. F. ( 1987) Dev. Biol. 120, 366–376.
15. Turner, D. L. & Cepko, C. L. ( 1987) Nature (London) 328, 131–136.
16. Turner, D. L., Snyder, E. Y. & Cepko, C. L. ( 1990) Neuron 4, 833–845.
17. Holt, C. E., Bertsch, T. W., Ellis, H. M. & Harris, W. A. ( 1988) Neuron 1, 15–26.
18. Fekete, D. M., Perez-Miguelsanz, J., Ryder, E. & Cepko, C. L. ( 1994) Dev. Biol. 166, 666–682.
19. Wetts, R. & Fraser, S. E. ( 1988) Science 239, 1142–1145.
20. Adler, R. & Hatlee, M. ( 1988) Science 243, 391–393.
21. Altshuler, D. & Cepko, C. ( 1992) Development (Cambridge, U.K.) 114, 947–957.
22. Lillien, L. & Cepko, C. ( 1992) Development (Cambridge, U.K.) 115, 253–266.
23. Sparrow, J. R., Hicks, D. & Barnstable, C. J. ( 1990) Dev. Brain Res. 51, 69–84.
24. Mack, A. F. & Fernald, R. D. ( 1991) J. Neurosci. Methods 36, 195–202.
25. Reh, T. A. ( 1992) J. Neurobiol. 23, 1067–1083.
26. Treisman, J. E., Morabito, M. A. & Barnstable, C. J. ( 1988) Mol. Cell. Biol. 8, 1570–1579.
27. Watanabe, T. & Raff, M. C. ( 1990) Neuron 2, 461–467.