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

• DOI: 10.1371/journal.pone.0212553
• Publication Date: 2019-02-21T13:48:25Z
• Authors: Jean J. Kim; Jeffrey N. Savas; Meghan T. Miller; Xindao Hu; Cassiano Carromeu; Mathieu Lavallée-...; Beatriz C. G. Fre...; Alysson R. Muotri; John R. Yates; Anirvan Ghosh
• Keywords: MeCP2; Rett Syndrome; LIN28

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