Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation
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
Affiliations
Jialin Sun
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA
Sivan Osenberg
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA; Departments of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA
Austin Irwin
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA
Li-Hua Ma
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA; Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA
Nigel Lee
Departments of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA
Yangfei Xiang
Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
Feng Li
Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA; Center for Drug Discovery and Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
Ying-Wooi Wan
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
In-Hyun Park
Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
Mirjana Maletic-Savatic
Departments of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA; Corresponding author
Nurit Ballas
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA; Corresponding author
Summary: 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.
