The long-range goal of our laboratory is to determine how oligodendrocyte development, myelin synthesis and maintenance, and remyelination are regulated at the molecular, cellular and organismal level. In this application we propose to test the hypothesis that cyclic AMP (cAMP) and insulin-like growth factor I (IGF-I), which we have previously identified as key regulators of oligodendrocyte development and function, regulate myelin synthesis by promoting one or more of the following steps: the switching on of genes for myelin components; transcription of selected genes; accumulation of the relevant mRNAs; and synthesis or stabilization of myelin components. To enable an efficient and straightforward experimental approach to these questions, we propose to develop a novel in vitro system of immortal oligodendrocytes and oligodendrocyte progenitors, produced by transfection of cells with an oncogene whose expression can be turned on by the investigator to achieve unlimited proliferation of clonally pure cells, and then turned off to allow expression only of endogenous cellular genes. (We will also produce clones of mouse oligodendrocytes and human oligodendrocytes for use as experimental material in other studies.) We will expose the cells in vitro to IGF-I or cAMP analogs and apply biochemical, immunochemical, cell biological and molecular genetic techniques to determine (1) at what step(s) the inducers act to promote myelin-associated functions, and (2) how the induction occurs. From these investigations, we expect to learn the molecular and biochemical basis for the regulation of oligodendrocyte development and the synthesis of myelin components by two potent regulatory agents. The results should give valuable insight into how myelination is controlled, and will be useful in attempting to understand the defects that occur in disorders of myelin. Moreover, the results may ultimately lead to the development of approaches to promoting remyelination in MS or other disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026119-02
Application #
3411768
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wiemelt, A P; Engleka, M J; Skorupa, A F et al. (1997) Immunochemical visualization and quantitation of cyclic AMP in single cells. J Biol Chem 272:31489-95
McMorris, F A; McKinnon, R D (1996) Regulation of oligodendrocyte development and CNS myelination by growth factors: prospects for therapy of demyelinating disease. Brain Pathol 6:313-29
Vemuri, G S; McMorris, F A (1996) Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival. Development 122:2529-37
Shinar, Y; McMorris, F A (1995) Developing oligodendroglia express mRNA for insulin-like growth factor-I, a regulator of oligodendrocyte development. J Neurosci Res 42:516-27
Raible, D W; McMorris, F A (1993) Oligodendrocyte differentiation and progenitor cell proliferation are independently regulated by cyclic AMP. J Neurosci Res 34:287-94
McMorris, F A; Mozell, R L; Carson, M J et al. (1993) Regulation of oligodendrocyte development and central nervous system myelination by insulin-like growth factors. Ann N Y Acad Sci 692:321-34
Carson, M J; Behringer, R R; Brinster, R L et al. (1993) Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 10:729-40
Mozell, R L; McMorris, F A (1991) Insulin-like growth factor I stimulates oligodendrocyte development and myelination in rat brain aggregate cultures. J Neurosci Res 30:382-90
Raible, D W; McMorris, F A (1990) Induction of oligodendrocyte differentiation by activators of adenylate cyclase. J Neurosci Res 27:43-6
McMorris, F A; Furlanetto, R W; Mozell, R L et al. (1990) Regulation of oligodendrocyte development by insulin-like growth factors and cyclic nucleotides. Ann N Y Acad Sci 605:101-9

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