Leukemia/lymphoma-related factor regulates oligodendrocyte lineage cell differentiation in developing white matter

Leukemia/lymphoma-related factor (LRF) is a zinc-finger transcription factor that regulates differentiation and oncogenesis in multiple tissues and cell lineages. The potential role for LRF in cells of the CNS has not been examined to date. This study shows prominent nuclear expression of LRF in diverse neuronal populations and in oligodendrocytes. We focused on examining the function of LRF during the transition from oligodendrocyte progenitor (OP) to mature oligodendrocyte that is associated with myelination in the postnatal spinal cord. During spinal cord myelination, LRF is expressed in only a minority of OP cells whereas most mature oligodendrocytes exhibited nuclear LRF immunoreactivity. Mice with floxed alleles of the Zbtb7a gene, which encodes for LRF protein, were used for in vivo analysis of LRF function. Lentiviral driven Cre recombinase inactivation of LRF at postnatal day 7 reduced the proportion of OP cells that differentiated into mature oligodendrocytes by postnatal day 28. Astrocyte populations were not altered by LRF deletion in the same tissues. These results indicate that LRF deletion reduces differentiation within the oligodendrocyte lineage and does not alter OP lineage choice. In vitro analysis confirmed a specific effect of LRF on OP differentiation. In neonatal OP cultures, RNA interference targeting LRF inhibited OP differentiation while LRF transduction was sufficient to induce differentiation into oligodendrocytes. These results support a critical role for LRF in transcriptional control of differentiation in oligodendrocyte lineage cells during developmental myelination in the CNS.