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

PloS One
Jean J KimAnirvan Ghosh

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 progenitor...Continue Reading

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Citations

May 29, 2020·Molecular Autism·Suzy Varderidou-MinasianVivi M Heine
Feb 12, 2021·International Journal of Molecular Sciences·Baiyan Ren, Anna Dunaevsky
Dec 15, 2020·Molecular Autism·Arquimedes ChefferOliver Brüstle
Apr 13, 2021·Frontiers in Cell and Developmental Biology·Samantha N Lanjewar, Steven A Sloan
Mar 24, 2020·Journal of Proteome Research·Spencer ChiangZheng Ouyang
Sep 14, 2021·Frontiers in Neuroscience·Florencia D HaaseWendy A Gold

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Methods Mentioned

BETA
flow cytometry
FACS
ChIP-seq
immunoprecipitation
ChIP
transfections
PCR

Software Mentioned

COR
ProLucid
SEQUEST
Li
DTASelect
SILAC
Census
QuantCompare
DTASelect2

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