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Matheus, F. ; Rusha, E. ; Rehimi, R.* ; Molitor, L. ; Pertek, A. ; Modic, M.* ; Feederle, R. ; Flatley, A. ; Kremmer, E. ; Geerlof, A. ; Rishko, V. ; Rada-Iglesias, A.* ; Drukker, M.

Pathological ASXL1 mutations and protein variants impair neural crest development.

Stem Cell Rep. 12, 861-868 (2019)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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The neural crest (NC) gives rise to a multitude of fetal tissues, and its misregulation is implicated in congenital malformations. Here, we investigated molecular mechanisms pertaining to NC-related symptoms in Bohring-Opitz syndrome (BOS), a developmental disorder linked to mutations in the Polycomb group factor Additional sex combs-like 1 (ASXL1). Genetically edited human pluripotent stem cell lines that were differentiated to NC progenitors and then xenotransplanted into chicken embryos demonstrated an impairment of NC delamination and emigration. Molecular analysis showed that ASXL1 mutations correlated with reduced activation of the transcription factor ZIC1 and the NC gene regulatory network. These findings were supported by differentiation experiments using BOS patient-derived induced pluripotent stem cell lines. Expression of truncated ASXL1 isoforms (amino acids 1-900) recapitulated the NC phenotypes in vitro and in ovo, raising the possibility that truncated ASXL1 variants contribute to BOS pathology. Collectively, we expand the understanding of truncated ASXL1 in BOS and in the human NC.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Asxl1 ; Bohring-opitz Syndrome ; Neural Crest ; Polycomb ; Zic1; Regulators; Identity; Genes
Language english
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 2213-6711
Journal Stem Cell Reports
Quellenangaben Volume: 12, Issue: 5, Pages: 861-868 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Maryland Heights, MO
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
Institute of Structural Biology (STB)
CF Monoclonal Antibodies (CF-MAB)
Institute of Molecular Immunology (IMI)
POF-Topic(s) 30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30203 - Molecular Targets and Therapies
30201 - Metabolic Health
Research field(s) Stem Cell and Neuroscience
Enabling and Novel Technologies
Helmholtz Diabetes Center
Immune Response and Infection
PSP Element(s) G-500800-001
G-552400-001
G-503091-001
G-502210-001
G-501793-001
G-503000-001
G-501760-001
DOI 10.1016/j.stemcr.2019.03.006
WOS ID WOS:000467952400001
Scopus ID 85065136433
PubMed ID 31006630
Erfassungsdatum 2019-05-07
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