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Modeling Rett Syndrome with Human Induced Pluripotent Stem Cells

  • Author(s): Ohashi, Minori
  • Advisor(s): Lowry, William
  • et al.

Rett syndrome is a neurodevelopmental disorder that predominately affects females and is one of the most common causes of intellectual disability in females. The syndrome is characterized by developmental stagnation, cognitive deficits, seizures and other autism-like symptoms. In more than 95% of cases, Rett syndrome results from de novo mutations in the gene encoding methyl CpG binding protein 2 (MECP2), which is found on the X chromosome. However, despite numerous studies implicating the loss of this protein in

Rett syndrome disease pathology, the precise reason why loss of MECP2 expression causes these clinical symptoms remains unclear. To further determine the role for mutations of MECP2 in Rett syndrome, we have generated isogenic lines of human induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts that either express or lack MECP2 to minimize genetic variability. Our data showed the neurons derived from NPCs adopted typical morphologies regardless of MECP2 expression, and all NPCs produced neurons and glia at the same rate. In patient iPSC-derived neurons, loss of MECP2 was correlated with Akt deactivation and reduced dendritic complexity. Molecular profiling uncovered a reduction of 5hmC, increased expression of subtelomeric genes, and shortening of telomeres in the absence of MECP2 in hiPSCs, NPCs, and neurons. Neurons made without MECP2 show signs of stress, including induction of gamma-H2aX, p53, and senescence, which are typical molecular responses to telomere shortening. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. Examination of Rett patient brains uncovered similar molecular phenotypes suggesting that our disease-in-a-dish model yielded insights into authentic human Rett syndrome patient phenotypes. These data point towards a role for MECP2 in regulating telomeres and could form a molecular basis for a new understanding of the etiology of Rett syndrome.

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