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Dev Cell. 2017 Jul 10;42(1):52-67.e4. doi: 10.1016/j.devcel.2017.06.009.

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage.

Author information

1
Department of Neurology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
2
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
3
Department of Neurology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; VAAAHS, University of Michigan Medical School, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Electronic address: dauer@med.umich.edu.

Abstract

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.

KEYWORDS:

DYT6; THAP1; YY1; dystonia; movement disorder; myelination; neurodevelopmental disorder; oligodendrocyte development; transcription factor

PMID:
28697333
PMCID:
PMC5847273
DOI:
10.1016/j.devcel.2017.06.009
[Indexed for MEDLINE]
Free PMC Article

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