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dc.contributor.authorLiu, Min
dc.contributor.authorXu, Ping
dc.contributor.authorGuan, Zhenlong
dc.contributor.authorQian, Xiaohong
dc.contributor.authorDockery, Peter
dc.contributor.authorFitzgerald, Una
dc.contributor.authorO'Brien, Timothy
dc.contributor.authorShen, Sanbing
dc.date.accessioned2018-09-20T16:14:44Z
dc.date.available2018-09-20T16:14:44Z
dc.date.issued2017-10-16
dc.identifier.citationLiu, Min; Xu, Ping; Guan, Zhenlong; Qian, Xiaohong; Dockery, Peter; Fitzgerald, Una; O'Brien, Timothy; Shen, Sanbing (2017). ulk4 deficiency leads to hypomyelination in mice. Glia 66 (1), 175-190
dc.identifier.issn0894-1491
dc.identifier.urihttp://hdl.handle.net/10379/12472
dc.description.abstractBrain nerve fibers are insulated by myelin which is produced by oligodendrocytes. Defects in myelination are increasingly recognized as a common pathology underlying neuropsychiatric and neurodevelopmental disorders, which are associated with deletions of the Unc-51-like kinase 4 (ULK4) gene. Key transcription factors have been identified for oligodendrogenesis, but little is known about their associated regulators. Here we report that Ulk4 acts as a key regulator of myelination. Myelination is reduced by half in the Ulk4(tm1a/tm1a) hypomorph brain, whereas expression of axonal marker genes Tubb3, Nefh, Nefl and Nefm remains unaltered. Transcriptome analyses reveal that 8 (Gfap, Mbp, Mobp, Plp1, Slc1a2, Ttr, Cnp, Scd2) of the 10 most significantly altered genes in the Ulk4(tm1a/tm1a) brain are myelination-related. Ulk4 is co-expressed in Olig2(+) (pan-oligodendrocyte marker) and CC1(+) (mature myelinated oligodendrocyte marker) cells during postnatal development. Major oligodendrogeneic transcription factors, including Olig2, Olig1, Myrf, Sox10, Sox8, Sox6, Sox17, Nkx2-2, Nkx6-2 and Carhsp1, are significantly downregulated in the mutants. mRNA transcripts enriched in oligodendrocyte progenitor cells (OPCs), the newly formed oligodendrocytes (NFOs) and myelinating oligodendrocytes (MOs), are significantly attenuated. Expression of stage-specific oligodendrocyte factors including Cspg4, Sox17, Nfasc, Enpp6, Sirt2, Cnp, Plp1, Mbp, Ugt8, Mag and Mog are markedly decreased. Indirect effects of axon caliber and neuroinflammation may also contribute to the hypomyelination, as Ulk4 mutants display smaller axons and increased neuroinflammation. This is the first evidence demonstrating that ULK4 is a crucial regulator of myelination, and ULK4 may therefore become a novel therapeutic target for hypomyelination diseases.
dc.publisherWiley-Blackwell
dc.relation.ispartofGlia
dc.subjecthypomyelination
dc.subjectknockout mice
dc.subjectoligodendrogenesis
dc.subjectulk4
dc.subjectwhite matter integrity
dc.subjectcentral-nervous-system
dc.subjecttranscription factor olig2
dc.subjectcorpus-callosum
dc.subjectwhite-matter
dc.subjectoligodendrocyte differentiation
dc.subjectin-vivo
dc.subjectengineered nanofibers
dc.subjectpostnatal-development
dc.subjectconditional knockout
dc.subjectbrain-development
dc.titleulk4 deficiency leads to hypomyelination in mice
dc.typeArticle
dc.identifier.doi10.1002/glia.23236
dc.local.publishedsourcehttp://onlinelibrary.wiley.com/doi/10.1002/glia.23236/pdf
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