Dataset Information

Human ESC-Derived Chimeric Mouse Models of Huntington's Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation.

ABSTRACT: Huntington's disease (HD) is characterized by hypomyelination and neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs) derived from mutant Huntingtin (mHTT) embryos or normal controls and performed RNA sequencing (RNA-seq) to assess mHTT-dependent changes in gene expression. In human GPCs (hGPCs) derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply downregulated relative to normal hESC GPCs; NKX2.2, OLIG2, SOX10, MYRF, and their downstream targets were all suppressed. Accordingly, when mHTT hGPCs were transplanted into hypomyelinated shiverer mice, the resultant glial chimeras were hypomyelinated; this defect could be rescued by forced expression of SOX10 and MYRF by mHTT hGPCs. The mHTT hGPCs also manifested impaired astrocytic differentiation and developed abnormal fiber architecture. White matter involution in HD is thus a product of the cell-autonomous, mHTT-dependent suppression of glial differentiation.

SUBMITTER: Osipovitch M

PROVIDER: S-EPMC6700734 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human ESC-Derived Chimeric Mouse Models of Huntington's Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation.

Osipovitch Mikhail M Asenjo Martinez Andrea A Mariani John N JN Cornwell Adam A Dhaliwal Simrat S Zou Lisa L Chandler-Militello Devin D Wang Su S Li Xiaojie X Benraiss Sarah-Jehanne SJ Agate Robert R Lampp Andrea A Benraiss Abdellatif A Windrem Martha S MS Goldman Steven A SA

Cell stem cell 20181213 1

Huntington's disease (HD) is characterized by hypomyelination and neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs) derived from mutant Huntingtin (mHTT) embryos or normal controls and performed RNA sequencing (RNA-seq) to assess mHTT-dependent changes in gene expression. In human GPCs (hGPCs) derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin ...[more]

PMID: 30554964

Similar Datasets

Project description:Huntington's disease (HD) patients suffer from progressive and debilitating motor dysfunction. Previously, we discovered reduced skeletal muscle chloride channel (ClC-1) currents, inwardly rectifying potassium (Kir) channel currents, and membrane capacitance in R6/2 transgenic HD mice. The ClC-1 loss-of-function correlated with increased aberrant mRNA processing and decreased levels of full-length ClC-1 mRNA (Clcn1 gene). Physiologically, the resulting muscle hyperexcitability may help explain involuntary contractions of HD. In this study, the onset and progression of these defects are investigated in R6/2 mice, ranging from 3 wk old (presymptomatic) to 9-13 wk old (late-stage disease), and compared with age-matched wild-type (WT) siblings. The R6/2 ClC-1 current density and level of aberrantly spliced Clcn1 mRNA remain constant with age. In contrast, the ClC-1 current density increases, and the level of aberrantly spliced Clcn1 mRNA decreases with age in WT mice. The R6/2 ClC-1 properties diverge from WT before the onset of motor symptoms, which occurs at 5 wk of age. The relative decrease in R6/2 muscle capacitance also begins in 5-wk-old mice and is independent of fiber atrophy. Kir current density is consistently lower in R6/2 compared with WT muscle. The invariable R6/2 ClC-1 properties suggest a disruption in muscle maturation, which we confirm by measuring elevated levels of neonatal myosin heavy chain (MyHC) in late-stage R6/2 skeletal muscle. Similar changes in ClC-1 and MyHC isoforms in the more slowly developing Q175 HD mice suggest an altered maturational state is relevant to adult-onset HD. Finally, we find nuclear aggregates of muscleblind-like protein 1 without predominant CAG repeat colocalization in R6/2 muscle. This is unlike myotonic dystrophy, another trinucleotide repeat disorder with similar ClC-1 defects, and suggests a novel mechanism of aberrant mRNA splicing in HD. These early and progressive skeletal muscle defects reveal much needed peripheral biomarkers of disease progression and better elucidate the mechanism underlying HD myopathy.

Dataset Information

Human ESC-Derived Chimeric Mouse Models of Huntington's Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation.

Publications

Human ESC-Derived Chimeric Mouse Models of Huntington's Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets