Modeling Rett syndrome with Patient-specific Induced Pluripotent Stem Cells

Rett syndrome (RTT) is one of the leading causes of intellectual disability in girls. Mutations in the X-linked methyl-CpG-binding protein 2 ( MECP2) gene have been identified as the cause of RTT. Mouse and patient-derived induced pluripotent stem cell (iPSC) model systems have been developed to better understand the molecular roles of MeCP2/MECP2 and gain insight on the disease pathophysiology. Recently, there has been an interest in the determining the glial component of RTT pathology. To model the non-cell autonomous glial component in RTT pathology in a human-based system, we have developed a patient-derived RTT astrocyte/neuron co-culture system. We have validated a detrimental non-cell autonomous effect of RTT astrocytes, and by utilizing three different RTT mutational lines, have determined that this effect is consistent and is mediated in part by astrocyte secreted factors. We have also gone on to test the efficacy of neurotrophic factors in ameliorating this glial effect and have found insulin-like growth factor 1 (IGF-1) and its tripeptide cleavage product, Glycine-Proline-Glutamate (GPE), to increase the somal area and to promote neurite outgrowth in GABAergic interneurons.