Retinoic acid regulates the development of oligodendrocyte precursor cells in vitro

Abstract

Cultures of oligodendrocyte precursor cells can be grown from brain hemispheres of newborn rats. These cells, also called O-2A progenitor cells, can differentiate in vitro into oligodendrocytes or type 2 astrocytes. Basic FGF and PDGF are known to stimulate their proliferation and delay their differentiation. Lack or excess of retinoic acid (RA) has been known for a long time to alter brain development suggesting that this compound is involved in normal brain development. Here we report that RA partially inhibits both the proliferation and the differentiation of oligodendrocyte precursor cells. It also down-regulates the mitogenic effect of bFGF on these cells while keeping them in an immature stage. RA is more effective than bFGF in inhibiting myelin basic protein mRNA expression in these cells, and like bFGF, it preserves their bipotential character. RA nuclear receptors RAR-alpha and their transcripts are expressed in oligodendrocyte precursor cells as seen by Western blot, Northern blot and in situ hybridization. The expression of RAR-alpha transcripts is stimulated transiently by RA alone or associated to bFGF. The expression of RAR-beta transcripts is not constitutive and is induced by RA alone or associated to bFGF and to a lesser extent by bFGF alone. These results suggest that retinoids participate in the control of the development of glial cells of the oligodendrocyte lineage.

K+Channel Expression and Cell Proliferation Are Regulated by Intracellular Sodium and Membrane Depolarization in Oligodendrocyte Progenitor Cells

“…Consistent with previous reports (Barres et al, 1994;Laeng et al, 1994;Noll and Miller, 1994), we found that RA treatment promoted a more bipolar morphology in O-2A cells (data not shown). Additionally, under culture conditions that promoted lineage progression (N1, PDGF, or bFGF), treatment with 1 M RA significantly decreased the percentage of O-2A cells that developed into O4 ϩ pro-oligodendroblasts (Fig.…”

“…A, An increase in the sustained current density was observed after culture in 45 mM [K ϩ ] o for 48 hr (see also Aii, Summary histograms of data obtained at a test pulse of ϩ70 mV reveals an upregulation of both the current amplitude and the current density when normalized for any changes in membrane capacitance. Bi, Similarly, an upregulation of the Kir current density was also observed after chronic exposure to 45 mM [K ϩ ] o culturing conditions (Bi,1,3,4 ) (see also (Barres et al, 1994;Laeng et al, 1994;Noll and Miller, 1994). The effects of RA on cell proliferation appear to be attributable, at least in part, to its action on voltage-dependent K ϩ channels, because O-2A cells cultured in RA displayed a significant downregulation of both sustained and transient K ϩ currents.…”

“…This makes cells of the oligodendrocyte lineage an ideal model to analyze the physiological role played by K ϩ channels during development and to study plastic changes in glial K ϩ current phenotype. O-2A cell proliferation is modulated by a variety of factors (McMorris and Dubois-Dalcq, 1988;Raff et al, 1988;Bogler et al, 1990;Hunter and Bottenstein, 1990;McKinnon et al, 1990;Barres et al, 1993;Gard and Pfeiffer, 1993;Hardy and Reynolds, 1993;Canoll et al, 1996) including retinoic acid (RA), which has been identified as an antimitotic agent that also inhibits O-2A differentiation (Barres et al, 1993;Laeng et al, 1994;Noll and Miller, 1994). Similar to RA treatment, we found that activation of glutamate receptors (GluRs) in O-2A cells inhibits proliferation stimulated by mitogenic factors and prevents lineage progression .…”

“…RA is known to regulate oligodendrocyte precursor development (Barres et al, 1993;Laeng et al, 1994;Noll and Miller, 1994). In agreement with previous studies on brain and spinal cord O-2A cells cultured with bFGF (Laeng et al, 1994;Noll and Miller, 1994), micromolar concentrations of RA inhibited cortical O-2A proliferation triggered by PDGF, bFGF, or PDGF ϩ bFGF, as measured by [ 3 H]thymidine incorporation (Fig. 9A).…”

Glucocorticoids and progestins signal the initiation and enhance the rate of myelin formation

“…Estradiol (40), retinoic acid (41), and thyroid hormone (14,21,42,43) have all been implicated in regulating the differentiation of glial cells in culture, suggesting an interaction of various hormones in the myelination process. Corticosteroids have played an important role in the diagnosis and therapy of demyelinating diseases (44)(45)(46) and have been found to modulate myelin proteins in oligodendrocytes (14,19).…”