Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture

Abstract

We have been studying a population of bipotential glial progenitor cells in the perinatal rat optic nerve and brain in an attempt to understand how cells choose between alternative fates in the developing mammalian central nervous system (CNS). This cell population gives rise initially to oligodendrocytes and then to type-2 astrocytes\ both of which apparently collaborate in sheathing axons in the CNS 2 .3. In vitro studies suggest that oligodendrocyte differentiation is the constitutive pathway of development for the oligodendrocyte-type-2-astrocyte (O-2A) progenitor ce1l 4 ,s, whereas type-2 astrocyte differentiation depends on a specific inducing protein 6 . This protein is present in the developing optic nerve when type-2 astrocytes are differentiating and can induce 0-2A progenitor cells in vitro to express glial fibrillary acidic protein (GFAP)6, a marker of astrocyte differentiation'. Here we show that the type-2-astrocyte-inducing protein is similar or identical to ciliary neutrotrophic factor (CNTF)8,9, which promotes the survival of some types of peripheral neurons in vitro 8 , including ciliary ganglion neurons8,IO. This suggests that CNTF, in addition to its effect on neurons, may be responsible for triggering type-2 astrocyte differentiation in the developing CNS.CNTF was purified from rat sciatic nerve using a modification of the method used previousll. When it was added to cultures of postnatal-day-O (PO) rat optic nerve cells it induced GFAP expression in about 20% of 0-2A progenitor cells (Fig. la). The same result was obtained with an extract of 3-4-week-old rat optic nerve (Fig. Ib), as described previously6. CNTF and optic nerve extract had the same effect when added simultaneously as when either was added alone (Fig. lb). Two other neurotrophic factors, nerve growth factor l1 ,12 and brain-derived growth factor 13 , had no effect on GFAP expression in this assay (not shown).CNTF and the type-2-astrocyte-inducing protein share several properties. They are both acidic (ref. 9 and unpublished observations), with a relative molecular mass (Mr) of about 25,000 (25K) (refs 6 and 9), and present at relatively high concentrations in sciatic nerve 6 ,l4 and kidney (ref. 9 and unpublished observations), compared with liver, retina or brain (refs 6, 14 and unpublished observations). If the type-2-astrocyte-inducing activity in optic nerve extracts is CNTF, then these extracts should support ciliary ganglion neuron survival in vitro, which they did (Fig. Id). The responses of both ciliary ganglion neurons and 0-2A progenitor cells were elicited within a similar range of concentrations (Fig. 1); the specific activity of optic nerve extract was about 1,300-fold less than that of CNTF in both assays.When tested on optic nerve cells CNTF had many of the functional properties previously described for optic nerve extract 6 • First, CNTF had no appreciable effect on GFAP expression in type-l astrocytes or their precursors in cultures of embryonic day 17 (E17) optic nerve cells, even though it induced many of ...

Isolation of a Novel Platelet-Derived Growth Factor-Responsive Precursor from the Embryonic Ventral Forebrain

“…Therefore, we reexamined the potential of PDGF-generated progeny to differentiate into astrocytes in the presence of CNTF, another factor known to induce astrocyte differentiation of O-2A progenitors (Hughes et al, 1988). We found that CNTF on its own did not induce GFAP expression in PDGF-generated progeny (Fig.…”

Apoptosis of Central and Peripheral Neurons Can Be Prevented with Cyclin‐Dependent Kinase/Mitogen‐Activated Protein Kinase Inhibitors

“…Paravertebral sympathetic ganglia, dorsal root ganglia, and ciliary ganglia were dissected from chick embryos at the indicated embryonic day as described elsewhere (Lindsay et al, 1985;Hughes et al, 1988). Embryos were staged (Hamburger and Hamilton, 1951) to confirm developmental age.…”

Developmental stage-dependent self-regulation of embryonic cortical precursor cell survival and differentiation by leukemia inhibitory factor

“…LIF acts as a survival factor for sensory and motor neurons in the mature nervous system (reviewed in Turnley and Bartlett 11 and Murphy et al 12 ). In the developing central nervous system (CNS), LIF 13,14 inhibits self-renewal of neural precursor cells and promotes differentiation into astrocytes, similar to other LIF/gp130-related cytokines such as ciliary neurotrophic factor (CNTF) [13][14][15][16] and oncostatin M. 17 However, recent data suggest an opposite effect of the signal in neural precursor cells, specifically the maintenance of cortical precursor cells 18,19 in the undifferentiated state by increasing their self-renewal and inhibiting progression to astrocytic lineage. The mechanism by which gp130/LIFR signal performs such opposite roles remains to be elucidated.…”