NEURAL PRECURSOR DIFFERENTIATION INTO ASTROCYTES REQUIRES SIGNALING THROUGH THE LEUKEMIA INHIBITORY FACTOR-RECEPTOR

The differentiation of precursor cells into neurons or astrocytes in t he developing brain has been thought to be regulated in part by growth factors. We show here that neural precursors isolated from the develo ping forebrain of mice that are deficient in the gene for the low-affi nity leukemia inhibitory factor receptor (LIFR-/-) fail to generate as trocytes expressing glial fibrillary acidic protein (GFAP) when cultur ed in vitro, Precursors from mice heterozygous for the null allele sho w normal levels of GFAP expression. These findings support the in vivo findings that show extremely low levels of GFAP mRNA in brains of emb ryonic day 19 LIFR-/- mice, In addition, monolayers of neural cells fr om LIFR-/- mice are far less able to support the neuronal differentiat ion 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 irre versibly blocked from differentiating into astrocytes: they express GF AP after long-term passaging or stimulation with bone morphogenetic pr otein-2, These findings strongly implicate the LIF family of cytokines in the regulation of astrocyte differentiation and indeed the LIF-def icient animals show a significant reduction in the number of GFAP cell s in the hippocampus. However, because this reduction is only partial it suggests that LIF may not be the predominant endogenous ligand sign aling through the LIFR.