Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice

Megan E Rowland; Yan Jiang; Sarfraz Shafiq; Alireza Ghahramani; Miguel A Pena-Ortiz; Vanessa Dumeaux; Nathalie G Bérubé

doi:10.1038/s41467-023-42752-y

Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice

Nat Commun. 2023 Nov 4;14(1):7090. doi: 10.1038/s41467-023-42752-y.

Authors

Megan E Rowland^{1

2}, Yan Jiang^{2

3}, Sarfraz Shafiq^{2

4}, Alireza Ghahramani^{2

4}, Miguel A Pena-Ortiz^{2

5}, Vanessa Dumeaux^{4

6}, Nathalie G Bérubé^{7

8

9

10

11}

Affiliations

¹ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
² Children's Health Research Institute, Division of Genetics & Development, London, ON, Canada.
³ Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁴ Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁵ Graduate Program in Neuroscience, Western University, London, ON, Canada.
⁶ Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁷ Children's Health Research Institute, Division of Genetics & Development, London, ON, Canada. nberube@uwo.ca.
⁸ Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. nberube@uwo.ca.
⁹ Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. nberube@uwo.ca.
¹⁰ Graduate Program in Neuroscience, Western University, London, ON, Canada. nberube@uwo.ca.
¹¹ Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. nberube@uwo.ca.

Abstract

Myelin, an extension of the oligodendrocyte plasma membrane, wraps around axons to facilitate nerve conduction. Myelination is compromised in ATR-X intellectual disability syndrome patients, but the causes are unknown. We show that loss of ATRX leads to myelination deficits in male mice that are partially rectified upon systemic thyroxine administration. Targeted ATRX inactivation in either neurons or oligodendrocyte progenitor cells (OPCs) reveals OPC-intrinsic effects on myelination. OPCs lacking ATRX fail to differentiate along the oligodendrocyte lineage and acquire a more plastic state that favors astrocytic differentiation in vitro and in vivo. ATRX chromatin occupancy in OPCs greatly overlaps with that of the chromatin remodelers CHD7 and CHD8 as well as H3K27Ac, a mark of active enhancers. Overall, our data indicate that ATRX regulates the onset of myelination systemically via thyroxine, and by promoting OPC differentiation and suppressing astrogliogenesis. These functions of ATRX identified in mice could explain white matter pathogenesis observed in ATR-X syndrome patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology
Chromatin / metabolism
Humans
Male
Mice
Myelin Sheath* / metabolism
Neurogenesis
Neuroglia
Oligodendroglia / metabolism
Thyroxine* / metabolism
X-linked Nuclear Protein* / genetics
X-linked Nuclear Protein* / metabolism

Substances

Chromatin
Thyroxine
X-linked Nuclear Protein
Atrx protein, mouse

Supplementary concepts

ATR-X syndrome