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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Asxl1 ; Bohring-opitz Syndrome ; Neural Crest ; Polycomb ; Zic1; Regulators; Identity; Genes
Sprache englisch
Veröffentlichungsjahr 2019
HGF-Berichtsjahr 2019
ISSN (print) / ISBN 2213-6711
Zeitschrift Stem Cell Reports
Quellenangaben Band: 12, Heft: 5, Seiten: 861-868 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Maryland Heights, MO
Begutachtungsstatus Peer reviewed
Institut(e) 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
Forschungsfeld(er) Stem Cell and Neuroscience
Enabling and Novel Technologies
Helmholtz Diabetes Center
Immune Response and Infection
PSP-Element(e) 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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