DYT6型肌张力障碍蛋白THAP1调节少突胶质细胞谱系中的髓鞘形成。
The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage.
作者信息
Yellajoshyula Dhananjay, Liang Chun-Chi, Pappas Samuel S, Penati Silvia, Yang Angela, Mecano Rodan, Kumaran Ravindran, Jou Stephanie, Cookson Mark R, Dauer William T
机构信息
Department of Neurology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
出版信息
Dev Cell. 2017 Jul 10;42(1):52-67.e4. doi: 10.1016/j.devcel.2017.06.009.
The childhood-onset motor disorder DYT6 dystonia is caused by loss-of-function mutations in the transcription factor THAP1, but the neurodevelopmental processes in which THAP1 participates are unknown. We find that THAP1 is essential for the timing of myelination initiation during CNS maturation. Conditional deletion of THAP1 in the CNS retards maturation of the oligodendrocyte (OL) lineage, delaying myelination and causing persistent motor deficits. The CNS myelination defect results from a cell-autonomous requirement for THAP1 in the OL lineage and is recapitulated in developmental assays performed on OL progenitor cells purified from Thap1 null mice. Loss of THAP1 function disrupts a core set of OL maturation genes and reduces the DNA occupancy of YY1, a transcription factor required for OL maturation. These studies establish a role for THAP1 transcriptional regulation at the inception of myelination and implicate abnormal timing of myelination in the pathogenesis of childhood-onset dystonia.
儿童期起病的运动障碍DYT6肌张力障碍由转录因子THAP1的功能丧失突变引起，但THAP1参与的神经发育过程尚不清楚。我们发现THAP1对中枢神经系统成熟过程中髓鞘形成起始的时间至关重要。中枢神经系统中THAP1的条件性缺失会延缓少突胶质细胞（OL）谱系的成熟，延迟髓鞘形成并导致持续性运动缺陷。中枢神经系统髓鞘形成缺陷是由于OL谱系中对THAP1的细胞自主需求导致的，并且在从Thap1基因敲除小鼠纯化的OL祖细胞上进行的发育实验中得到了重现。THAP1功能的丧失破坏了一组核心的OL成熟基因，并降低了OL成熟所需的转录因子YY1的DNA占有率。这些研究确立了THAP1转录调控在髓鞘形成起始阶段的作用，并表明髓鞘形成时间异常与儿童期起病的肌张力障碍发病机制有关。
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