Neural crest multipotency and specification: power and limits of single cell transcriptomic approaches

Abstract

The neural crest is a unique population of multipotent cells forming in vertebrate embryos. Their vast cell fate potential enables the generation of a diverse array of differentiated cell types in vivo . These include, among others, connective tissue, cartilage and bone of the face and skull, neurons and glia of the peripheral nervous system (including enteric nervous system), and melanocytes. Following migration, these derivatives extensively populate multiple germ layers. Within the competent neural border ectoderm, an area located at the junction between the neural and non-neural ectoderm during embryonic development, neural crest cells form in response to a series of inductive secreted cues including BMP, Wnt, and FGF signals. As cells become progressively specified, they express transcriptional modules conducive with their stage of fate determination or cell state. Those sequential states include the neural border state, the premigratory neural crest state, the epithelium-to-mesenchyme transitional state, and the migratory state to end with post-migratory and differentiation states. However, despite the extensive knowledge accumulated over 150 years of neural crest biology, many key questions remain open, in particular the timing of neural crest lineage determination, the control of potency during early developmental stages, and the lineage relationships between different subpopulations of neural crest cells. In this review, we discuss the recent advances in understanding early neural crest formation using cutting-edge high-throughput single cell sequencing approaches. We will discuss how this new transcriptomic data, from 2017 to 2021, has advanced our knowledge of the steps in neural crest cell lineage commitment and specification, the mechanisms driving multipotency, and diversification. We will then discuss the questions that remain to be resolved and how these approaches may continue to unveil the biology of these fascinating cells.

Spatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis

“…However, despite advances in our knowledge of the mechanisms that control early CNCC fate decisions, limited information is available about how postmigratory CNCCs acquire cell-fate-specific programs 10 . Furthermore, the GRNs of postmigratory CNCCs at the single-cell level remain largely unknown 11 .…”

Time to go: neural crest cell epithelial-to-mesenchymal transition

“…With these studies, the once simple model of morphogens driving transcriptional regulator expression in NCCs has become more complex, suggesting waves of signaling rather than finite signals. More information on the roles of signaling pathways in NCC development can be found in detailed reviews ( Artinger and Monsoro-Burq, 2021 ; Rogers et al, 2012 ; Rogers and Nie, 2018 ; Williams and Bohnsack, 2019 ).…”

From neural border to migratory stage: A comprehensive single cell roadmap of the timing and regulatory logic driving cranial and vagal neural crest emergence

“…We tested it on another vertebrate organism, zebrafish, to evaluate its accuracy for NC annotation. Our binary classifier determined whether a cell was NC or not, using our annotated frog whole embryo dataset at seven developmental stages (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The algorithm was tested on a zebrafish whole embryo SC dataset (21) at stage 14hpf (equivalent to frog stage 22) with a result of 0.95 for AUC score and 0.66 for F1 score (F1 score defines the weighted harmonic mean of the precision and recall, and it is equal to 0.05 for a random model applied to the zebrafish dataset, Fig.…”

“…During gastrulation (stages [11][12][13], the neural plate and the neural border zone are induced from the dorsal ectoderm due to BMP antagonists in the midline and Wnt/FGF signaling from the underlying mesoderm (18). As early as stage 10.5-11, the neural border initiates a few distinct gene expressions, such as pax3/7 (19).…”

“…at the neural border) would define the developmental genetic trajectories of the complete NC lineage tree. Most of the recent SC studies on NC cells have mainly explored NC after emigration (Artinger and Monsoro-Burq, 2021; Supplementary File 1 - Table S1). In contrast, pre-migratory NC single cells have received limited exploration, mostly around the EMT stage and on small cell numbers at a specific level of the body axis (Ling and Sauka-Spengler, 2019; Zalc et al, 2021).…”