TY - JOUR
T1 - Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function
AU - Kim, Jean J.
AU - Savas, Jeffrey N.
AU - Miller, Meghan T.
AU - Hu, Xindao
AU - Carromeu, Cassiano
AU - Lavallée-Adam, Mathieu
AU - Freitas, Beatriz C.G.
AU - Muotri, Alysson R.
AU - Yates, John R.
AU - Ghosh, Anirvan
N1 - Funding Information:
This work was supported by grants from the California Institute for Regenerative Medicine (CIRM) TR2-01814 and TR4-06747 (to A.R.M), and RB3-05229 (to A.G. and J.J.K.). The Muotri lab is supported by National Institutes of Health (NIH) through the NIH Director’s New Innovator Award Program (1-DP2-OD006495-01), an R01 MH100175-01 from NIMH and from the International Rett Syndrome Foundation (IRSF grant # 2915). J.N.S. was supported by an F. Hoffman-La Roche Postdoctoral Fellowship Award (SFP2063), 1K99DC013805-01 from National Institute on Deafness and Other Communication Disorders, and The Hartwell Foundation, Individual Biomedical Research Award. M.L.-A. was supported by a postdoctoral fellowship from the Fonds de Recherche du Québec–Nature et Technologies (FRQNT). The Yates’ lab is supported by UOW/R41GM103533, MH–2 R01 MH067880-11 and 1 R01 MH100175-01, and National Institute of General Medical Sciences P41 GM103533. The funder (F. Hoffmann-La Roche) provided support in the form of salaries for authors (MTM and AG), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
Publisher Copyright:
© 2019 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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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U2 - 10.1371/journal.pone.0212553
DO - 10.1371/journal.pone.0212553
M3 - Article
C2 - 30789962
AN - SCOPUS:85061920968
VL - 14
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 2
M1 - e0212553
ER -