Expression and imprinting of the insulin-like growth factor II gene in neonatal mouse cerebellum.

Insulin-like growth factor II (IGF-II) plays significant roles in the growth and development of mammals through the regulation of mitogenesis and cell survival. Previously, IGF-II mRNA transcripts within the CNS were detected in the choroid plexus and leptomeninges (DeChiara et al., 1991). The objective of this study was to determine the expression pattern of IGF-II mRNA in different cell types of the cerebellum during development. We report here that the IGF-II gene is transcribed in granule and glial cells within the cerebellar parenchyma at various times during the early postnatal period in mice. IGF-II gene expression is further regulated by parent-specific imprinting such that only the paternal IGF-II allele is expressed in granule cells. In contrast, choroid plexus and leptomeninges express IGF-II mRNAs biallelically, indicating that cell type-specific regulation of genomic imprinting occurs within the mammalian CNS.

Regulation of oligodendrocyte development and central nervous system myelination by insulin-like growth factors.

In summary, our studies show that IGFs are potent regulators of oligodendrocyte development and myelination in vitro and in vivo. IGFs act at several levels: by promoting proliferation of oligodendrocytes and oligodendrocyte precursors, by inducing immature oligodendrocyte precursors to develop into oligodendrocytes, and by regulating myelin gene expression and the amount of myelin produced per oligodendrocyte. Our findings indicate that IGFs play a crucial role in normal oligodendrocyte development and myelination, and suggest that IGFs may have applications for the promotion of remyelination in myelin disorders such as MS.

Insulin-like growth factor I stimulates oligodendrocyte development and myelination in rat brain aggregate cultures.

Insulin-like growth factor I (IGF-I) and high concentrations of insulin have been shown to stimulate an increase in the number of oligodendrocytes that appear in developing monolayer cultures of rat brain cells (McMorris et al., Proc Natl Acad Sci USA 83: 822-826, 1986; McMorris et al., Ann NY Acad Sci 605:101-109, 1990; McMorris and Dubois-Dalcq, J Neurosci Res 21:199-209, 1988). In the present study, we investigated whether IGF-I or insulin treatment induces a corresponding increase in the synthesis and accumulation of myelin. Aggregate cultures, established from 16-day-old fetal rat brains, were treated with either 100 ng/ml IGF-I or 5,000 ng/ml insulin and analyzed for the number of oligodendrocytes, activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP), total amount of myelin, and synthesis rate of myelin proteins. Cultures treated with IGF-I beginning on day 2 after explantation contained 35-80% more oligodendrocytes and had 60-160% higher CNP activity than controls when tested on day 13, 20, or 27. By day 27, treated cultures had 35-90% more myelin than controls. Similar results were observed in response to 5,000 ng/ml insulin, a concentration at which insulin binds to IGF receptors and acts as an analogue of IGF-I. The synthesis rate of myelin proteins was measured in experiments using 5,000 ng/ml insulin. When treatment was begun at day 20 rather than day 2, cultures did not exhibit an increased number of oligodendrocytes over control during the following 4-6 days.(ABSTRACT TRUNCATED AT 250 WORDS)