Review
Sox proteins and neural crest development

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Abstract

Among the families of transcription factors expressed at the neural plate border in response to neural crest-inducing signals, Sox proteins have emerged as important players in regulating multiple aspects of neural crest development. Here, we summarize the expression of six Sox genes, namely Sox8, Sox9, Sox10, LSox5, Sox4 and Sox11, in neural crest progenitors and their derivatives, and review some aspects of their function pertaining to neural crest development in several species.

Introduction

At the end of gastrulation, the ectoderm of the vertebrate embryo can be divided into three major domains: the non-neural ectoderm, the neural crest and the neural plate. The neural crest is induced at the lateral edge of the neural plate through interactions with surrounding tissues. While the precise nature of the neural crest-inducing signals derived from these tissues is not yet fully understood, there is strong evidence from work in several organisms that Notch signaling and members of the Bmp, Fgf and Wnt families are implicated in this process (reviewed in [1], [2]). While non-neural ectoderm and neural plate primarily give rise to epidermis and central nervous system respectively, cells of the neural crest contribute to many different lineages of the embryo. Around the time of neural tube closure and as they initiate their migration into the periphery, neural crest cells progressively adopt specific fates as a result of both intrinsic and extrinsic influences. Among others, the neural crest contributes to spinal ganglia, connective tissue, facial cartilage and bone, pigment cells, and enteric ganglia. With the exception of a region anterior to the diencephalon, neural crest arises from the entire length of the neural tube. However, neural crest from different axial levels gives rise to distinct derivatives. For example, hindbrain-derived neural crest cells migrate into pharyngeal arches to produce specific craniofacial skeletal elements, while neural crest cells in the trunk region form sensory neurons and glia.

One of the immediate consequences of the induction of the neural crest is the activation of a large number of “crest-specific” genes at the neural plate border. These factors belong to multiple families of transcriptional regulators [2], [3], [4]. Among these, several belong to the Sox (Sry HMG-box) family of transcription factors [5]. Sox genes are part of a larger family of high-mobility group (HMG) proteins, defined by their electrophoretic mobility on SDS-PAGE. Sox proteins bind DNA by means of the HMG domain, allowing them to function as transcription factors. This domain is highly conserved among Sox factors and all Sox proteins appear to recognize a similar motif on the DNA (A/T)(A/T)CAA(A/T)G. According to their sequence homologies within and outside the HMG domain, Soxs have been classified into groups A–H with Sry, the sex determining factor and founding member of this family, being assigned to the SoxA group [6]. Any given Sox factor is expressed in more than one cell type. For instance, Sox9 is expressed in developing chondrocytes and in Sertoli cells of the developing testis [7], [8], [9], [10], whereas Sox4 is expressed in the embryonic heart and adult pre-B and pre-T cells [11]. Considering (i) that all Sox proteins recognize a similar DNA binding motif; (ii) that each Sox factor is expressed in a variety of cell types; and (iii) that any given cell may co-express several Sox proteins, it is believed that Sox factors require interaction with cell type specific partner molecules to activate the appropriate set of genes [12], [13].

The first evidence for a role of Sox proteins in neural crest development came from the discovery that the neural crest phenotype observed in the Dominant megacolon (Dom) mice was linked to a mutation in the Sox10 gene [14], [15]. The Dom mice were discovered as a spontaneous mutation at the Jackson Laboratory and have been, for many years, a mouse model for the Waardenburg-Shah syndrome type IV. This neurocristopathy combines the features of the Waardenburg syndrome [16] and Hirschsprung's disease [17]. The pathologies associated with this disease include sensorineural deafness and pigmentation defects characteristic of the Waardenburg syndrome and aganglionic megacolon more specific to Hirschsprung's disease. Subsequently, Sox10 mutations were identified in a number of patients affected by Waardenburg-Shah syndrome type IV (reviewed in [18]). In the last 5 years, a number of studies in fish, frog, chick and mouse have identified several Sox family members expressed in neural crest progenitors and their derivatives. These genes appear to play important functions during the steps leading to neural crest specification, migration and differentiation. In this review, we present a summary of the most recent findings on the role of Sox proteins during neural crest development.

Section snippets

Sox genes expression in neural crest progenitors and their derivatives

Four major Sox genes are expressed at the neural plate border: Sox8, Sox9 and Sox10, which belong to the SoxE group, and LSox5, which belongs to the SoxD group. While they all show expression in neural crest progenitors at some point following neural crest induction, there are also some differences in the onset and the sequence of induction of these genes across species. Fig. 1 summarizes the onset of expression of several Sox genes in zebrafish, Xenopus, chick and mouse neural crest

Sox function in neural crest development

Combinations of knockout, knockdown and gain of function approaches have been developed to address Sox function in neural crest development. Table 2 is an attempt to summarize these studies in different species. In the next sections, we briefly describe some of these findings for each individual Sox gene.

Perspectives

Despite the large body of work generated in the last few years on the role of Sox proteins in neural crest development, still a great deal of work is needed to fully understand the function of this important class of transcription factors in the multiple steps leading to neural crest induction and diversification. Common themes in Sox function during neural crest development include survival, migration, differentiation and maintenance of multipotency. Several of the Sox genes expressed in the

Acknowledgements

We thank Dr. Trish Labosky and Christine Credidio for comments on the manuscript and Dr. Young-Hoon Lee for help in the preparation of Fig. 2B. We apologize to colleagues whose work is not cited due to space limitations.

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