Migration deficits of the neural crest caused by CXADR triplication in a human Down syndrome stem cell model

Abstract

Down syndrome (DS) is the most common chromosomal abnormality in live-born infants and is caused by trisomy of chromosome 21. Most individuals with DS display craniofacial dysmorphology, including reduced sizes of the skull, maxilla, and mandible. However, the underlying pathogenesis remains largely unknown. Since the craniofacial skeleton is mainly formed by the neural crest, whether neural crest developmental defects are involved in the craniofacial anomalies of individuals with DS needs to be investigated. Here, we successfully derived DS-specific human induced pluripotent stem cells (hiPSCs) using a Sendai virus vector. When DS-hiPSCs were induced to differentiate into the neural crest, we found that trisomy 21 (T21) did not influence cell proliferation or apoptosis. However, the migratory ability of differentiated cells was significantly compromised, thus resulting in a substantially lower number of postmigratory cranial neural crest stem cells (NCSCs) in the DS group than in the control group. We further discovered that the migration defects could be partially attributed to the triplication of the coxsackievirus and adenovirus receptor gene (CXADR; an adhesion protein) in the DS group cells, since knockdown of CXADR substantially recovered the cell migratory ability and generation of postmigratory NCSCs in the DS group. Thus, the migratory deficits of neural crest cells may be an underlying cause of craniofacial dysmorphology in individuals with DS, which may suggest potential targets for therapeutic intervention to ameliorate craniofacial or other neural crest-related anomalies in DS.

The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast

“…The model presented here-that particular genes become problematic in the context of aneuploidy-has important implications for studies on aneuploidy toxicity, including the etiology of human aneuploidy syndromes. For example, many DS studies interrogating single genes on human chromosome 21 probe effects through single-gene duplication in euploid cell lines (59)(60)(61)(62)(63). Our results raise caution about modeling these phenotypes in euploids and, as other have noted (64), underscore the importance of considering the cellular context of aneuploidy.…”

Long-read sequencing reveals the complex structure of extra dic(21;21) chromosome and its biological changes

“…and chromosome 21 open reading frame 91 (C21orf91), are related to neurogenesis [22][23][24][25] . The upregulation of CXADR during early brain development is associated with migration defects that cause craniofacial dysmorphology in DS 23 and developmental disorders 26 . C21orf91 is reported to be associated with brain development and intellectual disability based on the similarity between DS patients and other partial tetrasomy 21 (containing ampli cation of C21orf91) patients lacking DS phenotypes 24,27,28 .…”

“…and chromosome 21 open reading frame 91 (C21orf91), are related to neurogenesis [22][23][24][25] . The upregulation of CXADR during early brain development is associated with migration defects that cause craniofacial dysmorphology in DS 23 and developmental disorders 26 .…”

Long-read sequencing reveals the complex structure of extra dic(21;21) chromosome and its biological effects

“…We identified 11 protein-coding genes that showed an increased expression. Among them, four genes, RBM11 , CXADR Ig-Like Cell Adhesion Molecule ( CXADR ), BTG anti-proliferation factor 3 ( BTG3 ), and chromosome 21 open reading frame 91 ( C21orf91 ), are related to neurogenesis (Li et al 2016 , 2018 ; Liu et al 2022 ; Pedrotti et al 2012 ; Rost et al 2004; Slavotinek et al 2000 ; Yoshida et al 1998 ). Three other genes, NRIP1 , ATP synthetase peripheral stalk subunit F6 ( ATP5PF ), and GA binding protein transcription factor subunit alpha ( GABPA ), are associated with hypotonia in DS, which could be related to the patient’s severe delay in motor development (Brault et al 2015).…”