Olig2Ablation in Immature Oligodendrocytes Does Not Enhance CNS Myelination and Remyelination

Author:

Wang Jiajia,Yang Lijun,Jiang Mingqing,Zhao Chuntao,Liu Xuezhao,Berry Kalen,Waisman Ari,Langseth Abraham J.,Novitch Bennett G.,Bergles Dwight E.ORCID,Nishiyama AkikoORCID,Lu Q. RichardORCID

Abstract

The oligodendrocyte (OL) lineage transcription factor Olig2 is expressed throughout oligodendroglial development and is essential for oligodendroglial progenitor specification and differentiation. It was previously reported that deletion ofOlig2enhanced the maturation and myelination of immature OLs and accelerated the remyelination process. However, by analyzing multipleOlig2conditional KO mouse lines (male and female), we conclude that Olig2 has the opposite effect and is required for OL maturation and remyelination. We found that deletion ofOlig2in immature OLs driven by an immature OL-expressingPlp1promoter resulted in defects in OL maturation and myelination, and did not enhance remyelination after demyelination. Similarly,Olig2deletion during premyelinating stages in immature OLs usingMobporMogpromoter-driven Cre lines also did not enhance OL maturation in the CNS. Further, we found that Olig2 was not required for myelin maintenance in mature OLs but was critical for remyelination after lysolecithin-induced demyelinating injury. Analysis of genomic occupancy in immature and mature OLs revealed that Olig2 targets the enhancers of key myelination-related genes for OL maturation from immature OLs. Together, by leveraging multiple immature OL-expressing Cre lines, these studies indicate that Olig2 is essential for differentiation and myelination of immature OLs and myelin repair. Our findings raise fundamental questions about the previously proposed role of Olig2 in opposing OL myelination and highlight the importance of using Cre-dependent reporter(s) for lineage tracing in studying cell state progression.SIGNIFICANCE STATEMENTIdentification of the regulators that promote oligodendrocyte (OL) myelination and remyelination is important for promoting myelin repair in devastating demyelinating diseases. Olig2 is expressed throughout OL lineage development. Ablation ofOlig2was reported to induce maturation, myelination, and remyelination from immature OLs. However, lineage-mapping analysis ofOlig2-ablated cells was not conducted. Here, by leveraging multiple immature OL-expressing Cre lines, we observed no evidence thatOlig2ablation promotes maturation or remyelination of immature OLs. Instead, we find that Olig2 is required for immature OL maturation, myelination, and myelin repair. These data raise fundamental questions about the proposed inhibitory role of Olig2 against OL maturation and remyelination. Our findings highlight the importance of validating genetic manipulation with cell lineage tracing in studying myelination.

Funder

The national MS society

Publisher

Society for Neuroscience

Subject

General Neuroscience

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