Pathological ASXL1 Mutations and Protein Variants Impair Neural Crest Development.
Stem Cell Reports
; 12(5): 861-868, 2019 05 14.
Article
em En
| MEDLINE
| ID: mdl-31006630
ABSTRACT
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Diferenciação Celular
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Craniossinostoses
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Perfilação da Expressão Gênica
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Células-Tronco Pluripotentes
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Deficiência Intelectual
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Mutação
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Crista Neural
Limite:
Animals
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Humans
Idioma:
En
Revista:
Stem Cell Reports
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Alemanha