Regulatory Logic Underlying Diversification of the Neural Crest

Abstract

The neural crest is a transient, multipotent population of cells that arises at the border of the developing nervous system. After closure of the neural tube, these cells undergo an epithelial-to-mesenchymal transition (EMT) to delaminate and migrate, often to distant locations in the embryo. Neural crest cells give rise to a diverse array of derivatives including neurons and glia of the peripheral nervous system, melanocytes, and bone and cartilage of the face. A gene regulatory network (GRN) controls the specification, delamination, migration, and differentiation of this fascinating cell type. With increasing technological advances, direct linkages within the neural crest GRN are being uncovered. The underlying circuitry is useful for understanding important topics such as reprogramming, evolution, and disease.

Figure 1

Neural crest formation and its derivatives. (A) The neural crest forms by a series of important regulatory events: induction at the neural plate border, specification, delamination from the neural tube, migration throughout the embryo, and differentiation into many derivatives. During gastrulation, coordinated signaling events specify the region at the border between neural plate and non-neural ectoderm to promote neural crest formation. Initial specification of the neural crest from the neural plate border is complete when the neural folds become elevated during neurulation. In the chick, premigratory neural crest cells undergo an epithelial-to-mesenchymal transition (EMT) after neural tube closure to migrate extensively along distinct, stereotypical pathways to differentiate into a variety of derivatives. (B) Along the anterior-posterior length of the developing vertebrate embryo (left), different derivatives will form depending on the axial level (cranial, vagal, trunk, or sacral) from which they have originated. Neural crest cells at all axial levels contribute to melanocytes, the cranial neural crest gives rise to craniofacial skeleton, connective tissue, and cranial ganglia. The vagal neural crest cells contribute to the cardiac outflow tract and enteric nervous system. Trunk neural crest cells form dorsal root and sympathetic ganglia. Sacral neural crest cells will give rise to parts of the enteric and sympathetic nervous systems.

Figure 2

The GRN underlying neural crest development. Constructed from a systems-level amalgamation of literature in many vertebrate model systems, the neural crest GRN is comprised of sequential regulatory modules, focusing on transcription factors and signaling molecules for each stage of neural crest formation: induction, specification, delamination, migration, and differentiation. Differentiation gene batteries for five representative neural crest derivatives are placed downstream in the GRN hierarchy. Direct regulatory interactions within the neural crest GRN are represented by a solid line, while interactions that have yet to be verified as direct are represented with a dashed line. The GRN is largely conserved across vertebrates with some variation between species. For example, Twist1 is part of the neural crest specification module in frog and zebrafish, but missing in amniotes.