Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor - PubMed (original) (raw)

Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor

S A Koblar et al. Proc Natl Acad Sci U S A. 1998.

Abstract

The differentiation of precursor cells into neurons or astrocytes in the developing brain has been thought to be regulated in part by growth factors. We show here that neural precursors isolated from the developing forebrain of mice that are deficient in the gene for the low-affinity leukemia inhibitory factor receptor (LIFR-/-) fail to generate astrocytes expressing glial fibrillary acidic protein (GFAP) when cultured in vitro. Precursors from mice heterozygous for the null allele show normal levels of GFAP expression. These findings support the in vivo findings that show extremely low levels of GFAP mRNA in brains of embryonic day 19 LIFR-/- mice. In addition, monolayers of neural cells from LIFR-/- mice are far less able to support the neuronal differentiation of normal neural precursors than are monolayers from heterozygous or wild-type animals, indicating that endogenous signaling through the LIFR is required for the expression of both functional and phenotypic markers of astrocyte differentiation. LIFR-/- precursors are not irreversibly blocked from differentiating into astrocytes: they express GFAP after long-term passaging or stimulation with bone morphogenetic protein-2. These findings strongly implicate the LIF family of cytokines in the regulation of astrocyte differentiation and indeed the LIF-deficient animals show a significant reduction in the number of GFAP cells in the hippocampus. However, because this reduction is only partial it suggests that LIF may not be the predominant endogenous ligand signaling through the LIFR.

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Figures

Figure 1

Figure 1

Low levels of GFAP mRNA in LIFR−/− brain. mRNA was prepared from the brain, including forebrain, midbrain, and hindbrain of E19 littermates, and the presence of GFAP mRNA was determined by PCR.

Figure 2

Figure 2

Failure of LIFR−/− neural cells to express GFAP. Neuroepithelial cells from E12 forebrain were plated in vitro at a density of 2.5 × 104 per 200 mm2 into multiwell plates (Falcon 3047) and cultured for 20 days in the presence of serum. Cultures then were stained by immunoperoxidase for the presence of GFAP. The LIFR+/+ cultures contained large numbers of GFAP-positive cells (A and C) whereas the LIFR−/− cultures (B and C) contained few if any (<2 cells per well in every case). The data shown in C are the mean and SEM obtained from three separate experiments, each with three replicates.

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