Mutations in the Transcriptional Regulator MeCP2 Severely Impact Key Cellular and Molecular Signatures of Human Astrocytes During Maturation

Authors

Jialin Sun
Sivan Osenberg
Austin Irwin
Li-Hua Ma
Nigel Lee
Yangfei Xiang
Feng Li
Ying-Wooi Wan
In-Hyun Park
Mirjana Maletic-Savatic
Nurit Ballas

Publication Date

1-31-2023

Journal

Cell Reports

DOI

10.1016/j.celrep.2022.111942

PMID

36640327

PMCID

PMC10857774

PubMedCentral® Posted Date

2-9-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Astrocytes, Methyl-CpG-Binding Protein 2, Rett Syndrome, Neurons, Brain, Mutation

Abstract

Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether MECP2 mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing MECP2 mutations greatly impact the key role of astrocytes in regulating overall brain bioenergetics and that these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal maturation, astrocytes rely on neurons to induce their complex stellate morphology and transcriptional changes. While MECP2 mutations cause cell-intrinsic aberrations in the astrocyte transcriptional landscape, surprisingly, they do not affect the neuron-induced astrocyte gene expression. Notably, however, astrocytes are unable to develop complex mature morphology due to cell- and non-cell-autonomous aberrations caused by MECP2 mutations. Thus, MECP2 mutations critically impact key cellular and molecular features of human astrocytes and, hence, their ability to interact and support the structural and functional maturation of neurons.