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Stem Cell Reports. 2018 May 8;10(5):1453-1463. doi: 10.1016/j.stemcr.2018.04.001.

Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence.

Author information

1
Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA.
2
Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
3
Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
4
Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.
5
Department of Integrative Biology and Physiology, UCLA, Los Angeles, CA 90095, USA.
6
Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA. Electronic address: kplath@mednet.ucla.edu.
7
Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA. Electronic address: blowry@mcdb.ucla.edu.

Abstract

To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder.

KEYWORDS:

MECP2; Rett syndrome; disease in a dish; senescence

PMID:
29742391
PMCID:
PMC5995366
DOI:
10.1016/j.stemcr.2018.04.001
[Indexed for MEDLINE]
Free PMC Article

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