Astrocyte-derived TGFß2 and NGF Differentially Regulate Neural Recognition Molecule Expression by Cultured Astrocytes

Because of the importance of neural recognition molecules expressed by glial cells to mediate interactions with neurons, growth factors and cytokines known to be functional during morphogenesis and in diseases of the nervous system were studied for their effects on recognition molecule expression by cultured immature and mature astrocytes from several brain regions. In cultures of immature astrocytes, transforming growth factors-01 (TGF-ß1) and -ß2 (TGF-ß2) and nerve growth factor (NGF) increased expression of the neural adhesion molecule Ll, leading to a gliamediated Ll-specific increase in neurite outgrowth of dorsal root ganglion neurons on the astrocyte substrate. Ll expression induced by TGF-ß was inhibited by addition of antibodies to NGF, suggesting that TGF-ß influences Ll expression by modulating production of NGF by astrocytes . TGF-ßl and -ß2 decreased expression of N-CAM by immature astrocytes . Since N-CAM expression was not affected by NGF and antibodies to THE elucidation of the cellular and molecular mechanisms underlying neuronal survival, migration of neuronal cell bodies, and neurite outgrowth is not only pertinent for the understanding of neural development, but also for the understanding of degenerative and regenerative processes in the central and peripheral nervous systems of adult vertebrates. Growth factors and recognition molecules on the cell surface and in the extracellular matrix have both been implicated in morphogenetic processes (for reviews, see Barde, 1990 ; Schachner, 1990) . Neurotrophic factors, on the one hand, influence several cellular properties, among them neuronal survival and neurite outgrowth . On the other hand, neural recognition molecules have been implicated in neuronal migration and neurite outgrowth (for review, see Doherty and Walsh, 1989) . Evidence for a direct involvement ofrecognition molecules in cell survival is missing, although it is likely that they are also implicated in this phenomenon by virtue of their influence on second messenger systems (Schuch et al ., 1989) and the cytoskeleton (Pollerberg et al ., 1986) . Since both growth factors and recognition molecules are believed to mediate important morphogenetic processes, © The Rockefeller University Press, 0021-9525/91/10/473/12 $2 .00 TheJournal of Cell Biology, Volume 115, Number2, October 1991473-484 NGF did not abolish the TGF-ß-induced decrease in N-CAM expression, NGF did not appear to be the mediator for regulating expression of N-CAM. Expression of the adhesion molecule on glia (AMOG) was not affected by any factor. NGF and TGF-ß2 in latent form, but not TGF-ß 1 were found in the culture supernatants . Addition of interferon-y (IFN--y), interleukin-lß (IL-Iß), interleukin-6 (IL-6), platelet-derived growth factor (PDGF), or basic fibroblast growth factor (bFGF) to the cultures did not change recognition molecule expression . Recognition molecule expression by mature astrocytes was not found to be modified by any of the factors tested . In view of the observation that levels of Ll and N-CAM expression correlated with the presence of TGF-ß2 and NGF in the culture supernatants of immature astrocytes, an autocrine regulatory mechanism for recognition molecule expression by these cells is suggested to play a crucial role in regulation of neuron-glia interactions . it is plausible to assume that the two types of communication mechanisms between cells are interdependent and influence each other. However, relatively little attention has been given to this interdependence . First hints linking growth factor activity to recognition molecule expression stem from the observation that the nerve growth factor(NGF)l inducible large external glycoprotein NILE is related, if not identical to the recognition molecule L1 (Block et al ., 1985) . NGF enhances Ll expression not only in NGF receptor bearing neurons, but also in Schwann cells (Seilheimer and Schachner, 1987) . Since Ll mediates neurite outgrowth on other neurites and on Schwarm cells, most likely together with N-CAM by an assisted homophilic binding mechanism (Kadmon et al ., 1 . Abbreviations used in this paper: bFGF, basic fibroblast growth factor ; BME, basal modified Eagle's medium; CMF-HBSS, Cat+and Mg2+ -free HBSS ; EGF, epidermal growth factor ; GFAP, glial fibrillary acidic protein; IFN-y, interferon-y ; IL, interleukin ; L-TGF-ß, latent transforming growth factor-ß ; NGF, nerve growth factor ; TBS, Tris-buffered saline ; TGF, transforming growth factor. 473 on Jne 6, 2017 D ow nladed fom Published October 15, 1991