Leukemia inhibitory factor regulates the timing of oligodendrocyte development and myelination in the postnatal optic nerve.
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.
Ishibashi
Tomoko
T
Nervous System Development and Plasticity Section, National Institutes of Health, Bethesda, Maryland, USA.
Lee
Philip R
PR
Baba
Hiroko
H
Fields
R Douglas
RD
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D009900:Optic Nerve / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D053605:Leukemia Inhibitory Factor; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C507838:Lif protein, mouse; C512773:Olig2 protein, mouse