Temporal analysis of growth factor mRNA expression in myelinating rat brain aggregate cultures: Increments in CNTF, FGF-2, IGF-I, and PDGF-AA mRNA are induced by antibody-mediated demyelination

Myelinogenesis in rat brain aggregate cultures is associated with a pattern of growth factor mRNA expression comparable to that of the developing brai n. The rate of increase in platelet-derived growth factor-AA (PDGF-AA) expr ession was greatest just before the detection of myelin basic protein (MBP) mRNA in the cultures and remained high thereafter, consistent with in vivo observations. Levels of fibroblast growth factor-2 (FGF-2) and of ciliary neurotrophic factor (CNTF) mRNA increased continuously over the period of M BP accumulation. High rates of transforming growth factor beta 1 (TGF-beta 1), insulin-like growth factor-I (IGF-I), and neurotrophin-3 (NT-3) express ion at early time points during the culture gradually decreased over time, indicative of a key regulatory role during oligodendrocyte development. The addition of demyelinative anti-myelin oligodendrocyte glycoprotein (anti-M OG) antibody resulted in a significant increase in MBP peptide fragments wi th a C-terminus at phenylalanine 89 indicating proteolytic breakdown of MBP after myelin phagocytosis. Immediately after antibody treatment the expres sion of CNTF mRNA was significantly increased, compared with controls, whil e that of FGF-2 and IGF-I, and of PDGF-AA peaked during the early and later stages of recovery respectively. Thus, specific growth factors combine to regulate myelination and remyelination in the aggregates; these data have i mplications for demyelinating disease in which protective growth factor sec retion may be central to regeneration. (C) 2000 Wiley-Liss, Inc.