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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
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
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