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.     

SoxE factors function equivalently during neural crest and inner ear development and their activity is regulated by SUMOylation

Sox9 and the closely related factor Sox10 are essential for the formation of neural crest precursor cells, and play divergent roles in the process by which these cells are subsequently directed to form specific derivatives. These group E Sox factors have also been implicated in the development of the vertebrate inner ear. Despite their importance, however, the mechanisms that allow SoxE proteins to regulate such a diverse range of cell types have remained poorly understood. Here we demonstrate that during vertebrate development, the activities of individual SoxE factors are well conserved and are regulated by SUMOylation. We show that SoxE mutants that cannot be SUMOylated, or that mimic constitutive SUMOylation, are each able to mediate a subset of the diverse activities characteristic of wild-type SoxE proteins. These findings provide important mechanistic insight into how the activity of widely deployed developmental regulatory proteins can be directed to specific developmental events.     

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.     

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.     

The connectome of neural crest enhancers reveals regulatory features of signaling systems

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Cardiac neural crest

Neural crest cells (NCCs) contribute to many organs and tissues during embryonic development. Amongst these, the cardiovascular system represents a fascinating example. In this review, recent advances in our understanding of the developmental biology and molecular genetics regulating cardiac NCC maturation will be summarized. While the existence of a significant neural crest (NC) contribution to the developing heart has been appreciated for more than 20 years, only in the last few years have molecular pathways regulating this process been elucidated and the significant contribution of these mechanisms to the etiology of congenital heart disease in man become apparent. Emerging data suggest that ongoing studies will reveal complex inductive interactions between cardiac NC and a series of other cell types contributing to the developing cardiovascular system.     

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.     

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.