CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations

CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, and is characterized by a set of malformations that, on clinical grounds, were historically postulated to arise from defects in neural crest formation during embryogenesis. To better delineate neural crest defects in CHA...

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Published ineLife Vol. 6
Main Authors Okuno, Hironobu, Renault Mihara, Francois, Ohta, Shigeki, Fukuda, Kimiko, Kurosawa, Kenji, Akamatsu, Wado, Sanosaka, Tsukasa, Kohyama, Jun, Hayashi, Kanehiro, Nakajima, Kazunori, Takahashi, Takao, Wysocka, Joanna, Kosaki, Kenjiro, Okano, Hideyuki
Format Journal Article
LanguageEnglish
Published England eLife Sciences Publications Ltd 28.11.2017
eLife Sciences Publications, Ltd
Subjects
Biology
Cell migration
CHARGE syndrome
CHD7
Chromatin
Cloning
Defects
Developmental Biology
disease modeling
Embryogenesis
Experiments
Fibroblasts
Human Biology and Medicine
Hypotheses
induced pluripotent stem cells
Medicine
Mutation
Neural crest
Patients
Pluripotency
Software
Stem cells
Transplantation
human biology
stem cells
developmental biology
neural crest
CHD7
disease modeling
CHARGE syndrome
cell migration
induced pluripotent stem cells
medicine
human
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Summary:CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, and is characterized by a set of malformations that, on clinical grounds, were historically postulated to arise from defects in neural crest formation during embryogenesis. To better delineate neural crest defects in CHARGE syndrome, we generated induced pluripotent stem cells (iPSCs) from two patients with typical syndrome manifestations, and characterized neural crest cells differentiated in vitro from these iPSCs (iPSC-NCCs). We found that expression of genes associated with cell migration was altered in CHARGE iPSC-NCCs compared to control iPSC-NCCs. Consistently, CHARGE iPSC-NCCs showed defective delamination, migration and motility in vitro, and their transplantation revealed overall defective migratory activity in the chick embryo. These results support the historical inference that CHARGE syndrome patients exhibit defects in neural crest migration, and provide the first successful application of patient-derived iPSCs in modeling craniofacial disorders.
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ISSN:2050-084X
2050-084X
DOI:10.7554/elife.21114