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

Hironobu Okuno, Francois Renault Mihara, Shigeki Ota, Kimiko Fukuda, Kenji Kurosawa, Wado Akamatsu, Tsukasa Sanosaka, Jun Kohyama, Kanehiro Hayashi, Kazunori Nakajima, Takao Takahashi, Joanna Wysocka, Kenjiro Kosaki, Hideyuki Okano

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, 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 in ovo 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.

Original languageEnglish
Article numbere21114
JournaleLife
Volume6
DOIs
Publication statusPublished - 2017 Nov 28

Fingerprint

CHARGE Syndrome
Induced Pluripotent Stem Cells
Neural Crest
Stem cells
Mutation
Defects
Chick Embryo
Delamination
Chromatin
Embryonic Development
Cell Movement
Genes
Transplantation
Gene Expression

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

@article{43f99d7bc5cf4dafb726ae7dcc4c8ab5,
title = "CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations",
abstract = "CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, 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 in ovo 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.",
author = "Hironobu Okuno and Mihara, {Francois Renault} and Shigeki Ota and Kimiko Fukuda and Kenji Kurosawa and Wado Akamatsu and Tsukasa Sanosaka and Jun Kohyama and Kanehiro Hayashi and Kazunori Nakajima and Takao Takahashi and Joanna Wysocka and Kenjiro Kosaki and Hideyuki Okano",
year = "2017",
month = "11",
day = "28",
doi = "10.7554/eLife.21114",
language = "English",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations

AU - Okuno, Hironobu

AU - Mihara, Francois Renault

AU - Ota, Shigeki

AU - Fukuda, Kimiko

AU - Kurosawa, Kenji

AU - Akamatsu, Wado

AU - Sanosaka, Tsukasa

AU - Kohyama, Jun

AU - Hayashi, Kanehiro

AU - Nakajima, Kazunori

AU - Takahashi, Takao

AU - Wysocka, Joanna

AU - Kosaki, Kenjiro

AU - Okano, Hideyuki

PY - 2017/11/28

Y1 - 2017/11/28

N2 - CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, 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 in ovo 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.

AB - CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, 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 in ovo 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.

UR - http://www.scopus.com/inward/record.url?scp=85036494994&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85036494994&partnerID=8YFLogxK

U2 - 10.7554/eLife.21114

DO - 10.7554/eLife.21114

M3 - Article

C2 - 29179815

AN - SCOPUS:85036494994

VL - 6

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e21114

ER -