The International Journal of Biochemistry & Cell Biology
Molecules in focusSoxE factors as multifunctional neural crest regulatory factors
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)
- et al.
Sox10 regulates the development of neural crest-derived melanocytes in Xenopus
Dev Biol
(2003) - et al.
The transcriptional control of trunk neural crest induction, survival, and delamination
Dev Cell
(2005) - et al.
Sumoylation of the SOX10 transcription factor regulates its transcriptional activity
FEBS Lett
(2006) - et al.
Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton
Cell
(2001) - et al.
Sox proteins and neural crest development
Semin Cell Dev Biol
(2005) - et al.
Melanocyte-specific expression of dopachrome tautomerase is dependent on synergistic gene activation by the Sox10 and Mitf transcription factors
FEBS Lett
(2004) - et al.
The transcription factors L-Sox5 and Sox6 are essential for cartilage formation
Dev Cell
(2001) - et al.
SoxE factors function equivalently during neural crest and inner ear development and their activity is regulated by SUMOylation
Dev Cell
(2005) - et al.
Modulating the activity of neural crest regulatory factors
Curr Opin Genet Dev
(2007) - et al.
Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus
J Biol Chem
(2009)