Mowat-Wilson syndrome factor ZEB2 controls early formation of human neural crest through BMP signaling modulation.

Mowat-Wilson syndrome is caused by mutations in ZEB2, with patients exhibiting characteristics indicative of neural crest (NC) defects. We examined the contribution of ZEB2 to human NC formation using a model based on human embryonic stem cells. We found ZEB2 to be one of the earliest factors expressed in prospective human NC, and knockdown revealed a role for ZEB2 in establishing the NC state while repressing pre-placodal and non-neural ectoderm genes. Examination of ZEB2 N-terminal mutant NC cells demonstrates its requirement for the repression of enhancers in the NC gene network and proper NC cell terminal differentiation into osteoblasts and peripheral neurons and neuroglia. This ZEB2 mutation causes early misexpression of BMP signaling ligands, which can be rescued by the attenuation of BMP. Our findings suggest that ZEB2 regulates early human NC specification by modulating proper BMP signaling and further elaborate the molecular defects underlying Mowat-Wilson syndrome.

Distinct molecular profile and restricted stem cell potential defines the prospective human cranial neural crest from embryonic stem cell state.

Neural crest cells are an embryonic multipotent stem cell population. Recent studies in model organisms have suggested that neural crest cells are specified earlier than previously thought, at blastula stages. However, the molecular dynamics of early neural crest specification, and functional changes from pluripotent precursors to early specified NC, remain to be elucidated. In this report, we utilized a robust human model of cranial neural crest formation to address the distinct molecular character of the earliest stages of neural crest specification and assess the functional differences from its embryonic stem cell precursor. Our human neural crest model reveals a rapid change in the epigenetic state of neural crest and pluripotency genes, accompanied by changes in gene expression upon Wnt-based induction from embryonic stem cells. These changes in gene expression are directly regulated by the transcriptional activity of ß-catenin. Furthermore, prospective cranial neural crest cells are characterized by restricted stem cell potential compared to embryonic stem cells. Our results suggest that human neural crest induced by Wnt/ß-catenin signaling from human embryonic stem cells rapidly acquire a prospective neural crest cell state defined by a unique molecular signature and endowed with limited potential compared to pluripotent stem cells.