Assembling neural crest regulatory circuits into a gene regulatory network

Abstract

The neural crest is a multipotent stem cell–like population that gives rise to a wide range of derivatives in the vertebrate embryo including elements of the craniofacial skeleton and peripheral nervous system as well as melanocytes. The neural crest forms in a series of regulatory steps that include induction and specification of the prospective neural crest territory–neural plate border, specification of bona fide neural crest progenitors, and differentiation into diverse derivatives. These individual processes during neural crest ontogeny are controlled by regulatory circuits that can be assembled into a hierarchical gene regulatory network (GRN). Here we present an overview of the GRN that orchestrates the formation of cranial neural crest cells. Formulation of this network relies on information largely inferred from gene perturbation studies performed in several vertebrate model organisms. Our representation of the cranial neural crest GRN also includes information about direct regulatory interactions obtained from the cis-regulatory analyses performed to date, which increases the resolution of the architectural circuitry within the network.

Figure 1

A gene regulatory network (GRN) model (a view from all nuclei) that maps vertebrate hierarchical gene regulatory interactions during cranial neural crest cell (CNCC) development. The model is built using the BioTapestry software (Longabaugh et al. 2009). The GRN is partitioned into subnetworks that regroup regulatory interactions during induction and specification at the neural plate border, in premigratory and migrating neural crest cells, and in differentiating neural crest derivatives. Most of the linkages in the GRN model are inferred from available gene perturbation data from Xenopus, chicken, mouse, zebrafish, and lamprey. Direct regulatory interactions, based on promoter and cis-regulatory analysis, are indicated with solid lines. Dashed lines show potential direct regulatory interactions inferred from gene perturbation studies. Broken lines represent potential indirect interactions. Bubble nodes indicate protein-protein interactions. Transcriptional orientation was not taken into consideration because it varies among different vertebrate models.

Figure 2

A model of the GRN underlying CNCC formation that emphasizes only regulatory circuits with experimentally validated direct regulatory interactions.