A gene regulatory network orchestrates neural crest formation

The neural crest is a multipotent, migratory cell population that is unique to vertebrate embryos and gives rise to many derivatives, ranging from the peripheral nervous system to the craniofacial skeleton and pigment cells. A multimodule gene regulatory network mediates the complex process of neural crest formation, which involves the early induction and maintenance of the precursor pool, emigration of the neural crest progenitors from the neural tube via an epithelial to mesenchymal transition, migration of progenitor cells along distinct pathways and overt differentiation into diverse cell types. Here, we review our current understanding of these processes and discuss the molecular players that are involved in the neural crest gene regulatory network.     

Insights from a sea lamprey into the evolution of neural crest gene regulatory network

The neural crest is a vertebrate innovation that forms at the embryonic neural plate border, transforms from epithelial to mesenchymal, migrates extensively throughout the embryo along well-defined pathways, and differentiates into a plethora of derivatives that include elements of peripheral nervous system, craniofacial skeleton, melanocytes, etc. The complex process of neural crest formation is guided by multiple regulatory modules that define neural crest gene regulatory network (NC GRN), which allows the neural crest to progressively acquire all of its defining characteristics. The molecular study of neural crest formation in lamprey, a basal extant vertebrate, consisting in identification and functional tests of molecular elements at each regulatory level of this network, has helped address the question of the timing of emergence of NC GRN and define its basal state. The results have revealed striking conservation in deployment of upstream factors and regulatory modules, suggesting that proximal portions of the network arose early in vertebrate evolution and have been tightly conserved for more than 500 million years. In contrast, certain differences were observed in deployment of some neural crest specifier and downstream effector genes expected to confer species-specific migratory and differentiation properties.     

Modulating the activity of neural crest regulatory factors

Substantial progress has been made in defining the regulatory factors involved in generating multipotent neural crest cells at the neural plate border of vertebrate embryos, controlling the onset of their migratory behavior, and directing their differentiation into one of a diverse array of derivatives. Growing evidence suggests that these factors function as a complex network, in some cases displaying overlapping functions and cross-regulatory interactions. Mechanisms are emerging for how some of these regulatory components are controlled post-translationally and the extent to which their activities are conserved across species.     

The origin and evolution of the neural crest

Many of the features that distinguish the vertebrates from other chordates are derived from the neural crest, and it has long been argued that the emergence of this multipotent embryonic population was a key innovation underpinning vertebrate evolution. More recently, however, a number of studies have suggested that the evolution of the neural crest was less sudden than previously believed. This has exposed the fact that neural crest, as evidenced by its repertoire of derivative cell types, has evolved through vertebrate evolution. In this light, attempts to derive a typological definition of neural crest, in terms of molecular signatures or networks, are unfounded. We propose a less restrictive, embryological definition of this cell type that facilitates, rather than precludes, investigating the evolution of neural crest. While the evolutionary origin of neural crest has attracted much attention, its subsequent evolution has received almost no attention and yet it is more readily open to experimental investigation and has greater relevance to understanding vertebrate evolution. Finally, we provide a brief outline of how the evolutionary emergence of neural crest potentiality may have proceeded, and how it may be investigated.     

Comparison of evolutionary algorithms in gene regulatory network model inference

Background  

The evolution of high throughput technologies that measure gene expression levels has created a data base for inferring GRNs (a process also known as reverse engineering of GRNs). However, the nature of these data has made this process very difficult. At the moment, several methods of discovering qualitative causal relationships between genes with high accuracy from microarray data exist, but large scale quantitative analysis on real biological datasets cannot be performed, to date, as existing approaches are not suitable for real microarray data which are noisy and insufficient.     

Plasticity and regulatory mechanisms of Hox gene expression in mouse neural crest cells

In amniotes, the developmental potentials of neural crest cells differ between the cranium and the trunk. These differences may be attributable to the different expression patterns of Hox genes between cranial and trunk neural crest cells. However, little is known about the factors that control Hox genes expression in neural crest cells. The present data demonstrate that retinoic acid (RA) treatment and the activation of Wnt signaling induce Hoxa2 and Hoxd9 expression, respectively, in mouse mesencephalic neural crest cells, which never express Hox genes in vivo. Furthermore, Wnt signaling suppresses the induction of Hoxa2. We also demonstrate that these factors participate in the maintenance of Hoxa2 and Hoxd9 expression in mouse trunk neural crest cells. Our results suggest that RA and Wnt signaling function as environmental factors that regulate the expression of Hoxa2 and Hoxd9 in mouse neural crest cells.     

Latent homologues for the neural crest as an evolutionary novelty

The neural crest is a craniate synapomorphy and a bona fide evolutionary novelty. Recently, researchers considering intriguingly similar patterns of gene expression, cell behaviors, and embryogenetic processes in noncraniate deuterostomes have suggested that cephalochordates, urochordates, and echinoderms or their ancestors might have possessed cells that were precursors to the neural crest or its constituent cells. To emphasize the caution with which similarities at genetic, cellular, or embryological levels should be interpreted as substantiations for cell, germ layer, or tissue homologies, we present and evaluate additional tantalizing evidence that could be considered as documenting neural crest precursors in precraniates. Furthermore, we propose an evolutionary context--latent homologue--within which these data should be interpreted.     

Evidence for the neural crest origin of turtle plastron bones

Summary: The migrating cranial neural crest cells of birds, fish, and mammals have been shown to form the membranous bones of the cranium and face. These findings have been extrapolated to suggest that all the dermal bones of the vertebrate exoskeleton are derived from the neural crest ectomesenchyme. However, only one group of extant animals, the Chelonians, has an extensive bony exoskeleton in the trunk. We have previously shown that the autapomorphic carapacial and plastron bones of the turtle shell arise from dermal intramembranous ossification. Here, we show that the bones of the plastron stain positively for HNK‐1 and PDGFRα and are therefore most likely of neural crest origin. This extends the hypothesis of the neural crest origin of the exoskeleton to include the turtle plastron. genesis 31:111–117, 2001. © 2001 Wiley‐Liss, Inc.     

Ancient origin of the Hox gene cluster

The Hox gene cluster has a crucial function in body patterning during animal development. How and when this gene cluster originated is being clarified by recent data from Cnidaria, a basal animal phylum. The characterization of Hox-like genes from Hydra, sea anemones and jellyfish has revealed that a Hox gene cluster is extremely ancient, having originated even before the divergence of these basal animals.     

Cranial neural crest: Migratory cell behavior and regulatory networks

Defects of the head and neck region account for a substantial portion of all human birth disorders. The high incidence of malformations in this region may be attributed in part to the intricate means by which the facial region is assembled during embryonic development. The starting constituent for the majority of skeletal and connective tissues in the face is a pluripotent population of cells, the cranial neural crest (CNC) cells. This population of cells exhibit remarkable migratory abilities and diversity of potential cell types. This review draws on extensive research that has been done in the field, focusing specifically on findings generated in the last decade on cell behavior and the gene regulatory networks of migratory CNC cells. In the later part of this review, the importance of the CNC cells in the overall development of the craniofacial region will be illustrated with a discussion of a craniofacial birth defect, the Treacher Collins syndrome. The next decade will most likely herald in an era of greater understanding of the integrative molecular networks at different stages of the development of the CNC cells. Such new information is essential towards a better understanding the etiology and pathogenesis of the many craniofacial birth defects and will ultimately lead to new therapeutic modalities.