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

Jean J. Kim*, Jeffrey N. Savas, Meghan T. Miller, Xindao Hu, Cassiano Carromeu, Mathieu Lavallée-Adam, Beatriz C.G. Freitas, Alysson R. Muotri, John R. Yates, Anirvan Ghosh

*Corresponding author for this work

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3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0212553
JournalPloS one
Volume14
Issue number2
DOIs
StatePublished - Feb 2019

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Kim, J. J., Savas, J. N., Miller, M. T., Hu, X., Carromeu, C., Lavallée-Adam, M., Freitas, B. C. G., Muotri, A. R., Yates, J. R., & Ghosh, A. (2019). Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function. PloS one, 14(2), [e0212553]. https://doi.org/10.1371/journal.pone.0212553