A regulatory sub-circuit downstream of Wnt signaling controls developmental transitions in neural crest formation

Author summary The neural crest is a migratory stem cell population that plays a crucial role in the development of vertebrate embryos. These cells contribute to multiple tissues and organs, including the craniofacial skeleton, the peripheral nervous system, and the pigmentation of the skin. Neural crest formation requires sequential expression of sets of genes that gradually change the identity of progenitor cells. Here we characterize a gene circuit that plays an important role in these developmental transitions. We show that a pair of transcription factors downstream of the Wingless (Wnt) signaling pathway (SP5 and AXUD1) control the temporal activation of neural crest genes. While SP5 drives the expression of genes expressed at gastrula stages, AXUD1 promotes neural crest genes transcribed during neurulation. We found that these regulators are linked by inhibitory interactions that prevent overlap between transcriptional states. Our results shed light on how the architecture of gene regulatory circuits underlies the timing of developmental transitions during neural crest development. The process of cell fate commitment involves sequential changes in the gene expression profiles of embryonic progenitors. This is exemplified in the development of the neural crest, a migratory stem cell population derived from the ectoderm of vertebrate embryos. During neural crest formation, cells transition through distinct transcriptional states in a stepwise manner. The mechanisms underpinning these shifts in cell identity are still poorly understood. Here we employ enhancer analysis to identify a genetic sub-circuit that controls developmental transitions in the nascent neural crest. This sub-circuit links Wnt target genes in an incoherent feedforward loop that controls the sequential activation of genes in the neural crest lineage. By examining the cis-regulatory apparatus of Wnt effector gene AXUD1, we found that multipotency factor SP5 directly promotes neural plate border identity, while inhibiting premature expression of specification genes. Our results highlight the importance of repressive interactions in the neural crest gene regulatory network and illustrate how genes activated by the same upstream signal become temporally segregated during progressive fate restriction.

Automated summary

The neural crest, a migratory stem cell population crucial in vertebrate embryo development, undergoes sequential gene expression changes during its formation, leading to progressive fate restriction. A gene circuit involving SP5 and AXUD1 downstream of the Wnt signaling pathway controls the temporal activation of neural crest genes, with inhibitory interactions preventing overlap between transcriptional states. This study highlights the importance of repressive interactions in the neural crest gene regulatory network and the temporal segregation of genes activated by the same upstream signal during fate restriction.