Abstract
Glial fibrillary acidic protein (GFAP) is the main astroglial marker during astrogliogenesis, but it is also expressed in other cell types, including neural stem cells and old neurons. Activation of the JAK/STAT pathway by the IL-6 family of cytokines is the canonical pathway regulating GFAP expression, whereas retinoic acid is thought to be the only inducer of GFAP to operate independently of this pathway. Here, we show that retinoic acid receptor α not only links retinoic acid signaling to the canonical cytokine-stimulated pathway leading to GFAP expression but that it also plays a key role in the synergistic actions of retinoic acid and cytokines on this pathway. Cytokines both potentiate retinoic acid receptor α expression and enhance its binding to DNA and to the Stat3-p300/CBP-Smad transcriptional complex, the cornerstone of the canonical pathway. PI3K is upstream to all the key events leading to the expression of GFAP. Our results give new insights about the role of retinoic acid signaling in GFAP expression.
Highlights
The Glial fibrillary acidic protein (GFAP) is regulated in part by the secretion of factors into the extracellular space [7]
Retinoic acid inhibits GFAP-associated astrocyte differentiation induced by ciliary neurotrophic factor, an IL-6 family cytokine, in rat neural precursor cells isolated from embryonic day 13 brains but potentiates it in precursor cells from embryonic day 17 brains [16]
400 g these effects on GFAP expression are seen at physiological conof protein in 100 l of lysis buffer was incubated with the centrations of retinoic acid (Fig. 1D), indiselected antibodies overnight at 4 °C with rotation
Summary
Materials—The HCN-B27 clone of adult hippocampal precursor cells was isolated in our laboratory as described previously [23] as a subclone of the rat adult hippocampal precursor cell line (HCA) [15]. Procedures for cell culture were described elsewhere [14]. Cells were maintained in Neurobasal medium plus B27 supplement without antioxidants (Invitrogen) and seeded in DMEM/Ham’s F-12 1:1 medium plus N2.
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