Ciliary neurotrophic factor induces expression of the IGF type I receptor and FGF receptor 1 mRNAs in adult rat brain oligodendrocytes

Abstract

Ciliary neurotrophic factor (CNTF) is produced and released in response to injury in the central nervous system (CNS). While CNTF initially was characterized as a trophic factor for neurons, more recent evidence supports roles for this factor in survival, proliferation, and maturation of oligodendrocyte lineage cells. Evidence is emerging to support the hypothesis that CNTF's actions may include enhancing other growth and trophic factors. Here we tested the hypothesis that CNTF can induce expression of receptors on oligodendrocytes for factors that are known to promote their generation, maturation, and survival. Specifically, we used an in vivo paradigm to test whether CNTF, when injected stereotactically into forebrain white matter of adult rats, could induce mRNA expression for the insulin-like growth factor (IGF) type I receptor (IGF-IR), fibroblast growth factor (FGF) receptor (FGFR)-1, FGFR3, and platelet-derived growth factor (PDGF) receptor-alpha (PDGFRalpha). We determined that CNTF injection increased expression of IGF-IR and FGFR1 mRNAs in adult white matter to 200-250% of control levels. Cellular analysis indicated that these receptor mRNAs were induced in interfascicular oligodendrocytes. In contrast, CNTF had no effect on levels of FGFR3 and PDGFRalpha mRNAs. These results suggest that CNTF enhances the sensitivity of oligodendrocytes to other mitogens and trophic factors via induction of their receptors.

The Influence of Platelet-Derived Growth Factor and Fibroblast Growth Factor 2 on Oligodendrocyte Development and Remyelination

“…We demonstrate FGFR1 and FGFR3 expression by OPs, which we have previously shown express PDGFαR and exhibit vigorous proliferation during remyelination in this model (Redwine and Armstrong, 1998). We also show that in normal adult CNS, mature oligodendrocytes express FGFR3 in addition to previously reported expression of FGFR1 and/or FGFR2 (Asai et al, 1993;Yazaki et al, 1994;Gonzalez et al, 1995;Miyake et al, 1996;Belluardo et al, 1997;Redwine et al, 1997;Jiang et al, 1999). The differential expression of FGFR types by oligodendrocyte lineage cells may provide a mechanism for FGF2 to differentially influence proliferation, migration, differentiation and/or survival as required for oligodendrocyte lineage cells to repopulate lesions and accomplish stable remyelination.…”

“…FGF2 expression is subject to both transcriptional and translational control mechanisms (Touriol et al, 1999;Willis, 1999;Ueba et al, 1999), which may be influenced by environmental factors (Gomez-Pinilla and Dao, 1999;Jiang et al, 1999). Although we have not yet identified the molecular signals that trigger the observed upregulation of FGF2, the increased expression of FGF2 in this MHV-A59 model does not appear to reflect a response that is specific to this method of inducing demyelination, or to components specific to this lesion environment.…”

“…FGFR expression can be modulated by CNTF and FGF2 (Bansal et al, 1996;Bansal and Pfeiffer, 1997;Jiang et al, 1999), and therefore may be regulated by these and other cytokines and growth factors in the lesion environment. The functional results of FGF2 exposure can be diverse, and may depend upon the FGFR types expressed in conjunction with differential activation of intracellular signalling pathways within a given cell .…”

Mitogen‐activated protein kinase signalling in oligodendrocytes: a comparison of primary cultures and CG‐4

“…Furthermore, CNTF and LIF are well known OL survival factors: CNTF has been shown to enhance OL survival after TNF-a treatment or removal of trophic factors, and LIF has also been shown to promote OL survival in vitro (Barres et al, 1993;Louis et al, 1993;Mayer et al, 1994;D. Souza et al, 1996;Vos et al, 1996;Jiang et al, 1999). In CG-4, CNTF and LIF have been shown to enhance the survival of trophically deprived OL-like cells (Kahn and De Vellis, 1994).…”

Oligodendrocyte Fate after Spinal Cord Injury

“…CNTF and its receptor are upregulated early after SCI, and our laboratory detected a robust increase chronically in CNTF and its downstream signaling molecules along SCI lesion borders, which corresponds regionally and temporally to elevated OPC proliferation and maturation [67,89,97]. CNTF can also increase FGF-2 and receptors for FGF and IGF, thereby increasing the sensitivity of OL lineage cells to these factors [98,99]. The pronounced oligogenesis after injury in the astrocytic glial scar region, and the ability of astrocytes to secrete PDGF, FGF-2, IGF, and CNTF reveal astrocytes likely sit center stage in terms of influencing post-SCI OL production.…”