REGULATION OF FGF RECEPTORS IN THE OLIGODENDROCYTE LINEAGE

Fibroblast growth factors (FGFs) affect a broad spectrum of developmen tally regulated cellular responses involved in the control of growth a nd differentiation. To identify specific FGF receptor forms involved i n these responses, we have characterized FGF receptor transcript expre ssion, and its modulation by FGF-2, as enriched populations of oligode ndrocyte progenitors differentiate into mature oligodendrocytes. The d ata demonstrate that the levels of mRNA expression for FGF high-affini ty receptors-1, -2, and -3 are differentially regulated during lineage progression: FGF receptor-1 expression increases with lineage progres sion, FGF receptor-2 is predominantly expressed by terminally differen tiated oligodendrocytes, and FGF receptor-3 reaches a peak level of ex pression in late progenitors and then declines upon further differenti ation; FGF receptor-4 expression was not detected in oligodendrocytes. Distinct patterns of alternatively spliced variants of FGF receptor-1 and -2 transcripts are expressed: the predominant FGF receptor-1 tran scripts contain three Ig-like domains (FGF receptor-1 alpha), whereas the FGF receptor-2 transcripts contain two Ig-like domains (FGF recept or-2 beta 2) and this form is up-regulated as oligodendrocytes differe ntiate. In addition, the expression of these receptors is differential ly regulated by the ligand, FGF-2: FGF receptor-1 mRNA expression is u p-regulated in early progenitors, and FGF receptor-2 mRNA expression i s down-regulated in mature oligodendrocytes. Finally, astrocytes expre ss FGF receptor-1, -2, and -3 transcripts, but at different levels and with different exon utilization (FGF receptor-1 beta, FGF receptor-2 beta 1/beta 2) compared to oligodendrocytes. To our knowledge this is the first report that demonstrates that the mRNA expression of these t hree FGF receptor types is differentially regulated in primary cells a s they differentiate along a lineage from progenitors to terminally di fferentiated cells. We propose that this pattern of expression provide s a molecular basis for the developmentally varying response of cells to a common ligand. For example, according to this hypothesis, in resp onse to FGF-2, FGF receptor-1 transduces signals that stimulate the pr olonged proliferation and migration of early progenitors, FGF receptor -3 promotes the proliferation and arrest of differentiation of late pr ogenitors, and FGF receptor-2 transduces signals for terminal differen tiation, but not proliferation, in mature oligodendrocytes.