Molecules in focus
SoxE factors as multifunctional neural crest regulatory factors

https://doi.org/10.1016/j.biocel.2009.11.014Get rights and content

Abstract

Neural crest cells are the primary innovation that led to evolution of the vertebrates, and transcription factors of the SoxE family (Sox8, Sox9 and Sox10) are among the central players regulating the development of these cells. In all vertebrates examined to date, one or more SoxE proteins are required for the formation of neural crest cells, the maintenance of their multipotency, and their survival. Later, SoxE proteins drive the formation of multiple neural crest derivatives including chondrocytes, melanocytes, and cells of the peripheral nervous system, particularly Schwann cells/peripheral glia. Given their multiple diverse roles in the development of the neural crest, it is important to understand how the activity of SoxE factors is controlled such that they direct the correct developmental outcome. While combinatorial control with other regulatory factors is clearly one mechanism for generating such functional versatility, modulation of SoxE activity, both by SoxD family factors and by post-translational modification, also appears to be important. Elucidating the mechanisms that control SoxE function is essential to understand the evolutionary origin of the vertebrates, as well as a host of SoxE-linked syndromes and diseases, and may prove crucial for developing stem cell based therapies that target SoxE-regulated cell types.

Introduction

The neural crest (NC) is a population of multipotent precursor cells found at the crest of the closing neural folds in vertebrates. These cells undergo an epithelial to mesenchymal transition (EMT) and migrate extensively throughout the early embryo (Fig. 1A). Ultimately, NC cells differentiate into a diverse set of derivatives that includes neurons and glia of the peripheral nervous system (PNS), skin pigment cells, endocrine cells in the adrenal and thyroid glands, craniofacial cartilage and bone, smooth muscle and subregions of the cardiovasculature, among others (Le Douarin and Kalcheim, 1999) (Fig. 1B). A gene regulatory network controlling neural crest development has been described (Sauka-Spengler and Bronner-Fraser, 2008) and while multiple transcription factors are known to regulate this process, SoxE proteins are notable as the major class of transcriptional activators required for the formation of NC precursor cells (“neural crest specifiers”), in addition to the multiple roles they play in directing the formation of distinct NC derivatives. In this review we summarize our understanding of the reiterative roles that SoxE factors play in the process of NC development, and examine the regulatory processes that may contribute to their ability to carry out such diverse functions.

Section snippets

SoxE function in early neural crest formation

Once the neural plate border has been specified, SoxE family transcription factors are the earliest markers of the subset of these border cells competent to give rise to the definitive NC (Sauka-Spengler and Bronner-Fraser, 2008). In avians and mammals, Sox9 expression distinguishes NC precursor cells, whereas Sox8 does in Xenopus with Sox9 expression following soon after (Hong and Saint-Jeannet, 2005). Sox10 is expressed, or functions, somewhat later in NC precursors in most species and thus

SoxE function in neural crest diversification

Although it is extinguished in early migrating NC cells, Sox9 is subsequently expressed in cells that will form cartilage in most vertebrates (both NC- and non-NC-derived) and its role in cartilage formation has been highly studied. Mutations in human SOX9 cause the disease Campomelic Dysplasia (CD), symptoms of which include: skeletal malformation and craniofacial defects (Schafer et al., 1996). Sox9 directly regulates Type II collagen (Col2a1), one of the most important collagens in cartilage

Mechanisms for modulating SoxE activity

One means of modulating SoxE function appears to involve the Sox Group D factors Sox5 (L-Sox5) and Sox6. These three factors form a complex on the Col2a1 enhancer in chondrocytes (Zhou et al., 1998, Lefebvre et al., 1998). L-Sox5 and Sox6 preferentially bind HMG-like consensus sites in the Col2A1 enhancer as homodimers, and cooperatively enhance the activation of Col2A1 by Sox9 (Lefebvre et al., 1998). Consistent with an essential role for these factors, Sox5/Sox6 double mutant mice show a

Conclusions and perspectives

SoxE factors play multiple essential roles in NC formation, including conferring the competence for cells at the neural plate border to become NC precursors, maintaining the stem cell-like state of these cells, and promoting NC survival (Fig. 1A). These proteins are further involved in directing the formation of multiple NC derivatives including melanocytes, chondrocytes, and glia (Fig. 1B). This is not a surprising feature of SoxE proteins, as the myriad of cell fate decisions that take place

Acknowledgements

We apologize to colleagues whose work was not cited due to space constraints. We thank members of the lab for helpful suggestions, and Pei-Chih Lee and Kimberly Taylor for help with figures. Work in the authors’ laboratory was supported by RO1CA114058.

References (32)

  • G. Zhou et al.

    Three high mobility group-like sequences within a 48-base pair enhancer of the Col2a1 gene are required for cartilage-specific expression in vivo

    J Biol Chem

    (1998)
  • H. Akiyama et al.

    Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa

    Proc Natl Acad Sci USA

    (2004)
  • H. Akiyama et al.

    The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6

    Genes Dev

    (2002)
  • S. Elworthy et al.

    Transcriptional regulation of mitfa accounts for the sox10 requirement in zebrafish melanophore development

    Development

    (2003)
  • G. Gill

    SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?

    Genes Dev

    (2004)
  • X. Guo et al.

    Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation

    Genes Dev

    (2004)
  • Cited by (0)

    View full text