Leukemia inhibitory factor regulates the timing of oligodendrocyte development and myelination in the postnatal optic nerve

Abstract

Leukemia inhibitory factor (LIF) promotes the survival of oligodendrocytes both in vitro and in an animal model of multiple sclerosis, but the possible role of LIF signaling in myelination during normal development has not been investigated. We find that LIF -/-mice have a pronounced myelination defect in optic nerve at postnatal day 10. Myelin basic protein (MBP)-and proteolipid protein (PLP)-positive myelin was evident throughout the optic nerve in the wild-type mice, but staining was present only at the chiasmal region in LIF -/-mice of the same age. Further experiments suggest that the myelination defect was a consequence of a delay in maturation of oligodendrocyte precursor cell (OPC) population. The number of Olig2-positive cells was dramatically decreased in optic nerve of LIF -/-mice, and the distribution of Olig2-positive cells was restricted to the chiasmal region of the nerve in a steep gradient toward the retina. Gene expression profiling and cell culture experiments revealed that OPCs from P10 optic nerve of LIF -/-mice remained in a highly proliferative immature stage compared with littermate controls. Interestingly, by postnatal day 14, MBP immunostaining in the LIF -/-optic nerve was comparable to that of LIF +/+ mice. These results suggest that, during normal development of mouse optic nerve, there is a defined developmental time window when LIF is required for correct myelination. Myelination seems to recover by postnatal day 14, so LIF is not necessary for the completion of myelination during postnatal development. Keywords myelin; LIF; oligodendrocyte; astrocyte; optic nerve; transcription; OPC; differentiation Identifying the signals controlling oligodendrocyte differentiation and myelination is an important priority in current research in developmental neurobiology and in clinical research on demyelinating CNS disease. Cytokines have a well-appreciated role in inflammatory responses during nervous system injury and disease, but, in contrast to the case for growth factors and cell adhesion molecules, the possible role of cytokines in regulating oligodendrocyte development and myelination under normal physiological conditions is relatively unexplored. Based on recent research identifying LIF signaling between astrocytes and oligodendrocytes in regulating myelination in response to electrical activity in axons (Ishibashi et al.,[2006]), the present study was undertaken to investigate the possible role of *Correspondence to R. Douglas Fields, Nervous Systems Development and Plasticity Section, National Institutes of Health, NICHD Bldg. 35, Room 2A211, MSC 371335 Lincoln Drive, Bethesda, MD 20892. † The first two authors contributed equally to this work. LIF in regulating myelination of early postnatal optic nerve. Using genetic knockout mice, this study is the first analysis of LIF signaling on myelination during early postnatal development in the CNS. NIH Public AccessAlthough cytokines are generally associated with inflammatory disease, there is evidence that nervous system developmen...

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