CHD3 regulates BMP signalling response during cranial neural crest cell specification

CHD3 is a component of the NuRD chromatin remodeller. Mutations in CHD3 cause Snijders Blok-Campeau Syndrome, a neurodevelopmental disorder marked by intellectual disability and craniofacial abnormalities. To unveil the role of CHD3 in craniofacial development, we differentiated CHD3-null induced pluripotent stem cells (iPSCs) into cranial neural crest cells (CNCC). We found that CHD3 expression is low in iPSCs and neuroectoderm, but it is upregulated during CNCC specification, where CHD3-containing NuRD opens the chromatin at BMP-responsive enhancers, to allow binding of DLX5 and other factors. CHD3 loss leads to repression of BMP target genes and imbalance between BMP and Wnt signalling, which ultimately results in aberrant mesodermal fate. Consequently, cranial neural crest specification fails, replaced by mesodermal identity, which can be partially rescued by titrating Wnt levels. Our findings highlight a novel role for CHD3 as pivotal regulator of BMP signalling, essential for proper neural crest specification and craniofacial development.