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PLoS One. 2019 Feb 21;14(2):e0212553. doi: 10.1371/journal.pone.0212553. eCollection 2019.

Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function.

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Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America.
Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, United States of America.
Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.


Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation.

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Conflict of interest statement

Drs. Anirvan Ghosh and Meghan T. Miller were employed by F. Hoffmann-La Roche during the course of this study. This study was funded in part by F. Hoffmann-La Roche (Postdoctoral Fellowship to Dr. Jeffrey N. Savas). Dr. Alysson Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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