@article{c732c0963bc94156b09509276d25bc8b,
title = "The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage",
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",
author = "Dhananjay Yellajoshyula and Liang, {Chun Chi} and Pappas, {Samuel S.} and Silvia Penati and Angela Yang and Rodan Mecano and Ravindran Kumaran and Stephanie Jou and Cookson, {Mark R.} and Dauer, {William T.}",
note = "Funding Information: We are grateful to Dr. Roman Giger and Dr. Yevgeniya Mironova for providing us with many reagents and valuable discussions. We thank Alexander Hodge and Audrey Kim for technical assistance. We thank the laboratory of Dr. Stanley Watson for providing access to their microscope and support for the use of stereoinvestigator software. We thank Drs. Catherine Collins, Paul Jenkins, Roman Giger, and Tony Antonellis for critical reading of the manuscript. We thank the Jeff Harrison and Pennelope Blakely (MIL, University of Michigan), Hong Yi (EM Core, Emory University), and the rest of the staff of University of Michigan's Core Facilities (DNA Sequencing Core, Unit of Laboratory Animal Medicine) and the Gene Targeting and Transgenic Facility at UCONN Health. This research was supported in part by the following grants: RO1NS077730 to W.T.D. (NINDS), Dystonia Medical Research Foundation to W.T.D., UM Center for Organogenesis Training Program and NCATS (NIH, Award Number 2UL1TR000433) to D.Y., and Intramural Research Program of the NIH, National Institute on Aging to M.R.C. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jul,
day = "10",
doi = "10.1016/j.devcel.2017.06.009",
language = "English (US)",
volume = "42",
pages = "52--67.e4",
journal = "Developmental cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "1",
}