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

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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.

eLife digest

CHARGE syndrome is a disease in which organs including the heart, eyes and ears may not develop properly. The cells that form the tissues affected by CHARGE syndrome develop in embryos from precursor cells called neural crest cells. Individuals with CHARGE syndrome also have mutations in a gene called CHD7. However, it is difficult to examine how CHD7 mutations affect neural crest cells in embryos.

In recent years, cell reprogramming techniques have made it possible to create induced pluripotent stem cells (iPSCs) from the specialized somatic cells found in the human body. These iPSCs can be developed into many different cell types, including neural crest cells.

Okuno et al. created iPSCs from the skin cells of people with CHARGE syndrome, developed these cells into neural crest cells, and compared them with neural crest cells that were developed from the skin cells of people without CHARGE syndrome. The neural crest cells developed from people with CHARGE syndrome showed multiple abnormalities. For example, they were not able to move around correctly. This is an important observation because neural crest cells must move through tissues to form the various organs affected by CHARGE syndrome.

Okuno et al. also observed changes in the activity of many genes other than CHD7 in the neural crest cells developed from CHARGE patients. Further research is now needed to find out which genes are the most important for restoring the normal activity of neural crest cells.

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Most cited references 41

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SUMMARY The isolation of human induced pluripotent stem cells (iPSCs)1-3 offers a novel strategy for modeling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs4-7. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy caused by a point mutation in IKBKAP 8 involved in transcriptional elongation9. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood due to the lack of an appropriate model system. Here we report the derivation of patient specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC derived lineages demonstrates tissue specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell based assays revealing marked defects in neurogenic differentiation and migration behavior. Finally, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining novel insights into human disease pathogenesis and treatment.

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Neural crest cells (NCC) are a transient, embryonic cell population characterized by unusual migratory ability and developmental plasticity. To annotate and characterize cis-regulatory elements utilized by the human NCC, we coupled a hESC differentiation model with genome-wide profiling of histone modifications and of coactivator and transcription factor (TF) occupancy. Sequence analysis predicted major TFs binding at epigenomically annotated hNCC enhancers, including a master NC regulator, TFAP2A, and nuclear receptors NR2F1 and NR2F2. Although many TF binding events occur outside enhancers, sites coinciding with enhancer chromatin signatures show significantly higher sequence constraint, nucleosomal depletion, correlation with gene expression, and functional conservation in NCC isolated from chicken embryos. Simultaneous co-occupancy by TFAP2A and NR2F1/F2 is associated with permissive enhancer chromatin states, characterized by high levels of p300 and H3K27ac. Our results provide global insights into human NC chromatin landscapes and a rich resource for studies of craniofacial development and disease. Copyright © 2012 Elsevier Inc. All rights reserved.

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Hidenori Tabata, Kazunori Nakajima (2003)

Two distinct modes of radial neuronal migration, locomotion and somal translocation, have been reported in the developing cerebral cortex. Although these two modes of migration have been well documented, the cortical intermediate zone contains abundant multipolar cells, and they do not resemble the cells migrating by locomotion or somal translocation. Here, we report that these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers. Time-lapse analysis of living slices revealed that the multipolar cells do not have any fixed cell polarity, and that they very dynamically extend and retract multiple processes as their cell bodies slowly move. They do not usually move straight toward the pial surface during their radial migration, but instead frequently change migration direction and rate; sometimes they even remain in almost the same position, especially when they are in the subventricular zone. Occasionally, the multipolar cells jump tangentially during their radial migration. Because the migration modality of these cells clearly differs from locomotion or somal translocation, we refer to their novel type of migration as "multipolar migration." In view of the high proportion of cells exhibiting multipolar migration, this third mode of radial migration must be an important type of migration in the developing cortex.

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Author and article information

Contributors

Kenjiro Kosaki

Hideyuki Okano:

ORCID: https://orcid.org/0000-0001-7482-5935

Marianne Bronner: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 28 November 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e21114

Affiliations

[1 ]deptDepartment of Physiology Keio University School of Medicine TokyoJapan

[2 ]deptDepartment of Biological Science Tokyo Metropolitan University TokyoJapan

[3 ]deptDivision of Medical Genetics Kanagawa Children's Medical Center YokohamaJapan

[4 ]deptCenter for Genomic and Regenerative Medicine Juntendo University School of Medicine TokyoJapan

[5 ]deptDepartment of Anatomy Keio University School of Medicine TokyoJapan

[6 ]deptDepartment of Pediatrics Keio University School of Medicine TokyoJapan

[7 ]deptDepartment of Developmental Biology Stanford University School of Medicine StanfordUnited States

[8 ]Howard Hughes Medical Institute, Stanford University School of Medicine StanfordUnited States

[9 ]deptInstitute for Stem Cell Biology and Regenerative Medicine Stanford University School of Medicine StanfordUnited States

[10 ]deptDepartment of Chemical and Systems Biology Stanford University School of Medicine StanfordUnited States

[11 ]deptCenter for Medical Genetics Keio University School of Medicine TokyoJapan

California Institute of Technology United States

Author information

Hironobu Okuno http://orcid.org/0000-0003-1932-9482

Kazunori Nakajima https://orcid.org/0000-0003-1864-9425

Hideyuki Okano https://orcid.org/0000-0001-7482-5935

Article

Publisher ID: 21114

DOI: 10.7554/eLife.21114

PMC ID: 5705211

PubMed ID: 29179815

SO-VID: d47340f0-6015-4357-b00b-7b09286bcc7f

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 01 September 2016

Date accepted : 22 October 2017