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MeCP2 Dosage affects Cortical Organoid Physiology

  • Author(s): Chakoumakos, Madison Ann
  • Advisor(s): Muotri, Alysson R
  • et al.
Abstract

An optimal level of methyl-CpG binding protein 2 (MeCP2) is necessary for normal neurodevelopment. Researchers have shown that loss of MeCP2 leads to Rett syndrome, characterized by impaired motor function, loss of language, and autistic features. In contrast, increased MeCP2 dosage leads to MECP2 duplication syndrome which is similarly characterized by a severe neurodevelopmental phenotype with onset at birth. These disorders share some common clinical features; however, on the cellular level, studies have shown that these syndromes result in strikingly different cellular phenotypes. To further understand the effects of MeCP2 dosage on human neurons, we utilized induced pluripotent stem cell (iPSC) technology to generate human cortical organoids with varying levels of MeCP2. Specifically, we used CRISPR/Cas9 to generate human isogenic MECP2-duplication, wild-type, and knockout iPSC lines. To better represent neurodevelopment over using traditional 2-D iPSC methods, we differentiated these cell lines into cerebral organoids. Here, we report one of the first human stem cell models that elucidates the effects of MeCP2 dosage on cortical organoid physiology. We show that MeCP2 amount affects cortical organoid size, neural migration, neurite outgrowth, and neuroinflammation genes. Ultimately, we hope our work will provide further insight into the effects of MeCP2 dosage on neurodevelopment and provide a platform for drug discovery.

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