Pathological ASXL1 Mutations and Protein Variants Impair Neural Crest Development

• Published in: Stem cell reports 2019-05, Vol.12 (5), p.861-868
• Main Authors: Matheus, Friederike, Rusha, Ejona, Rehimi, Rizwan, Molitor, Lena, Pertek, Anna, Modic, Miha, Feederle, Regina, Flatley, Andrew, Kremmer, Elisabeth, Geerlof, Arie, Rishko, Valentyna, Rada-Iglesias, Alvaro, Drukker, Micha
• Format: Article
• Language: English
• Subjects: Animals; ASXL1; Bohring-Opitz syndrome; Cell Differentiation - genetics; Cell Line; Cells, Cultured; Chick Embryo; Craniosynostoses - genetics; Craniosynostoses - metabolism; Craniosynostoses - pathology; Gene Expression Profiling - methods; Gene Regulatory Networks; Human Embryonic Stem Cells - cytology; Human Embryonic Stem Cells - metabolism; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Intellectual Disability - genetics; Intellectual Disability - metabolism; Intellectual Disability - pathology; Mutation; neural crest; Neural Crest - cytology; Neural Crest - metabolism; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Polycomb; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transplantation, Heterologous; ZIC1
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.03.006

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. •Generation of human pluripotent stem cell models for Bohring-Opitz syndrome•ASXL1 mutations perturb neural crest (NC) emigration in vitro and in vivo•ASXL1 mutations correlate with impaired activation of ZIC1•Expression of truncated ASXL1 variants mirrors NC perturbation in vitro and in vivo In this study, Drukker and colleagues developed human pluripotent stem cell models for the rare congenital disorder Bohring-Opitz syndrome, which is caused by mutations in the Polycomb factor ASXL1. In these lines, they found impaired neural crest emigration in vitro and in vivo and link this phenotype to impaired activation of ZIC1.