Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
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.
Cell Rep. 2023 Jan 31;42(1):111942. doi: 10.1016/j.celrep.2022.111942. Epub 2023 Jan 5.
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.
MECP2 基因突变是一系列神经发育障碍的基础，最常见的是雷特综合征（RTT）。我们想知道 MECP2 突变是否会干扰人类星形胶质细胞的发育成熟，从而影响其支持神经元的能力。我们使用基于人类的模型表明，RTT 致病的 MECP2 突变极大地影响了星形胶质细胞在调节大脑整体生物能量方面的关键作用，并且这些代谢异常可能是由功能失调的线粒体介导的。在出生后成熟过程中，星形胶质细胞依赖神经元诱导其复杂的星状形态和转录变化。虽然 MECP2 突变导致星形胶质细胞的转录图谱出现细胞内异常，但令人惊讶的是，它们不会影响神经元诱导的星形胶质细胞基因表达。然而，值得注意的是，由于 MECP2 突变引起的细胞自主和非细胞自主异常，星形胶质细胞无法发育成复杂的成熟形态。因此，MECP2 突变严重影响了人类星形胶质细胞的关键细胞和分子特征，从而影响了它们与神经元相互作用和支持其结构和功能成熟的能力。
