SoxE factors as multifunctional neural crest regulatory factors

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.

Figure 1

Schematic overview of Neural Crest (NC) Development. (A) NC precursors with stem cell properties form at the border of the neural plate and non-neural ectoderm. Following neural tube closure, neural crest cells undergo an EMT and migrate throughout the embryo to points of differentiation. SoxE Proteins are required for the specification, precursor formation, survival and migration of NC cells throughout this process. (B) NC cells give rise to a diverse set of derivatives. SoxE proteins are required to direct the differentiation of multiple NC derivatives including glia, melanocytes and cartilage, and are also required for development of non-NC derivatives.

Figure 2

Model for regulation of SoxE protein function by SUMO during inductive events in the early ectoderm. In the absence of SUMO modification SoxE factors function as transcriptional activators and direct NC development at the expense of otic placode (ear). SUMOylation serves as a switch causing these proteins to inhibit NC formation and promote ear formation, most likely through the displacement of co-activators and the recruitment of new co-factors. (CBP/p300, activator protein; S, SUMO moiety; X, repressor protein; arrow on DNA indicates transcriptional activation of target genes, blunt arrow indicates transcriptional repression).