Martin Raff: Growth Control in Animal Development

I. Regulation of Cell Size
II. Cell Number Control

Part II: Cell Number Control

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Lecture Overview
The size of an organ or organism depends mainly on the sizes and numbers of the cells it contains. In the first segment of my talk, I describe our work on cell size control in cultures of purified rat Schwann cells. Most proliferating cells grow before they divide, but it is not known how growth and division are co-ordinated to ensure that cells divide at an appropriate size. We have found that extracellular signals can control cell growth and cell-cycle progression separately and that the size of Schwann cells at division depends on the signalled rates of both cell growth and cell-cycle progression, rather than on a cell-size checkpoint that monitors cell size.

In the second segment of my talk, I describe our work on cell number control in the rat oligodendrocyte cell lineage. Cell numbers depend on controls on both cell death and cell proliferation. We have found that oligodendrocytes are normally overproduced and kill themselves in large numbers in a competition for survival signals on the surface of the axons that the oligodendrocytes myelinate. Most differentiated cells, including oligodendrocytes, develop from dividing precursor cells that divide a limited number of times before they terminally differentiate, but it is not known what stops cell division and initiates differentiation. We have found that oligodendrocyte precursor cells have an intrinsic timing mechanism that helps determine when they stop dividing and differentiate.

Speaker Bio
Martin Raff was born and educated in Montreal. He received his BSc and MD degrees at McGill University and did a residency in medicine at the Royal Victoria Hospital in Montreal and in neurology at the Massachusetts General Hospital in Boston. He did postdoctoral training in immunology at the National Institute for Medical Research in London, after which he moved to University College London, where he has been a Professor of Biology since 1979 and emeritus since 2002. He is currently at the Medical Reseach Council Laboratory for Molecular Cell Biology and in the Biology Department at University College London. His research has been in immunology, cell biology, and developmental neurobiology.

He is a Fellow of the Royal Society, the Academy of Medical Sciences, and the Academia Europaea, a foreign member of the American Academy of Arts and Sciences, and a Foreign Associate of the National Academy of Sciences.

He was president of the British Society of Cell Biology from 1991 to 1995 and chairman of the UK Life Sciences Committee from 1998-2001. He is co-author of two widely used textbooks, Molecular Biology of the Cell and Essential Cell Biology.

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Reading  (for Part 1)
Metcalf, D. (1963). The autonomous behaviour of normal thymus grafts. Aust J Exp Biol Med Sci 41, 437-448.

Metcalf, D. (1964). Restricted growth capacity of multiple spleen grafts. Transplantation 2, 387-392.

Nurse, P., Thuriaux, P., and Nasmyth, K. (1976). Genetic control of the cell division cycle in the fission yeast Schizosaccharomyces pombe. Mol Gen Genet 146, 167-78.

Johnston, G. C., Pringle, J. R., and Hartwell, L. H. (1977). Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. Exp Cell Res 105, 79-98.

Brooks, R. F., and Shields, R. (1985). Cell growth, cell division and cell size homeostasis in Swiss 3T3 cells. Exp Cell Res 156, 1-6.

Franklin, J. L., and Johnson, E. M. (1998). Control of neuronal size homeostasis by trophic factor-mediated coupling of protein degradation to protein synthesis. J Cell Biol 142, 1313-24.

Conlon, I., and Raff, M.C. (1999) Size control in animal development. Cell 96: 235–244.

Conlon, I.J., Dunn, G.A., Mudge, A.W., and Raff, M.C. (2001) Extracellular control of cell size. Nature Cell Biol. 3: 918–21.

Saucedo LJ, Edgar BA. (2002) Why size matters: altering cell size. Curr Opin Genet Dev. 12:565-71.

Fingar, D. C., Salama, S., Tsou, C., Harlow, E., and Blenis, J. (2002). Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16, 1472-87.

Conlon I., and Raff, M. (2003) Differences in the way a mammalian cell and yeast cells coordinate cell growth and cell-cycle progression. J. Biol. 2: 7.1–7.9.

Reading (for Part 2)
Bryant, P.J., and Schmidt, O. (1990). The genetic control of cell proliferation in Drosophila imaginal discs. J Cell Sci Suppl 13, 169-189.

Temple, S., and Raff, M.C. (1986) Clonal analysis of oligodendrocyte development in culture: evidence for a developmental clock that counts cell divisions. Cell 44:773–779.

Barres, B.A., Hart, I.K., Coles, H.S.R., Burne, J.F., Voyvodic, J.T., Richardson, W.D., and Raff, M.C. (1992) Cell death and control of cell survival in the oligodendrocyte cell lineage. Cell 70:31–46.

Durand, B., Gao, F., and Raff, M. (1997) Accumulation of the cyclin-dependent kinase inhibitor p27/kip1 and the timing of oligodendrocyte differentiation. EMBO J. 16: 306-317.

Gao, F., Durand, B. and Raff, M. (1997) Oligodendrocyte precursor cells count time but not cell divisions before differentiation. Curr. Biol. 7:152-155.

Durand, B., Fero, M.L., Roberts, J.M., and Raff, M.C. (1998) p27/Kip1 alters the response of cells to mitogen and is part of a cell intrinsic timer that arrests the cell cycle and initiates differentiation. Curr. Biol. 8:431-440.

Calver, A. R., Hall, A. C., Yu, W. P., Walsh, F. S., Heath, J. K., Betsholtz, C., and Richardson, W. D. (1998). Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron 20, 869-82.

Fernandez, P-A., Tang, D.G., Cheng, L., Prochiantz, A., Mudge, A.W., and Raff, M.C. (2000) Evidendce that axon-derived neuregulin promotes oligodendrocyte survival in the developing rat optic nerve. Neuron 28: 81-90.

Kondo, T. and Raff, M. (2000) The Id4 HLH protein and the timing of oligodendrocyte differentiation EMBO J. 19: 1998-2007.

Barres, B.A. and Raff, M.C. (1999) Axonal control of oligodendrocyte development. J. Cell Biol. 147: 1123-1128.

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