Roles and regulation of SOX transcription factors in skeletogenesis

Abstract

SOX transcription factors participate in the specification, differentiation and activities of many cell types in development and beyond. The 20 mammalian family members are distributed into eight groups based on sequence identity, and while co-expressed same-group proteins often have redundant functions, different-group proteins typically have distinct functions. More than a handful of SOX proteins have pivotal roles in skeletogenesis. Heterozygous mutations in their genes cause human diseases, in which skeletal dysmorphism is a major feature, such as campomelic dysplasia (SOX9), or a minor feature, such as LAMSHF syndrome (SOX5) and Coffin-Siris-like syndromes (SOX4 and SOX11). Loss- and gain-of-function experiments in animal models have revealed that SOX4 and SOX11 (SOXC group) promote skeletal progenitor survival and control skeleton patterning and growth; SOX8 (SOXE group) delays the differentiation of osteoblast progenitors; SOX9 (SOXE group) is essential for chondrocyte fate maintenance and differentiation, and works in cooperation with SOX5 and SOX6 (SOXD group) and other types of transcription factors. These and other SOX proteins have also been proposed, mainly through in vitro experiments, to have key roles in other aspects of skeletogenesis, such as SOX2 in osteoblast stem cell self-renewal. We here review current knowledge of well-established and proposed skeletogenic roles of SOX proteins, their transcriptional and non-transcriptional actions, and their modes of regulation at the gene, RNA and protein levels. We also discuss gaps in knowledge and directions for future research to further decipher mechanisms underlying skeletogenesis in health and diseases and identify treatment options for skeletal malformation and degeneration diseases.

Keywords: Cell differentiation; Cell specification; Chondrocyte; Gene regulation; Osteoblast; SOX; Skeletogenesis; Transcription factor; Transcriptional regulation.

Fig. 1

General and specific properties of SOX transcription factors. (A) Rendering of the SOX4 HMG domain (rainbow-colored) bound to DNA (gray). The HMG domain has three α-helices that fold into an L-shape. It contacts DNA in the minor groove and induces a strong bend. Its N- and C-termini are indicated. This cartoon was generated by SWISS-MODEL using published data (Jauch, Ng, Narasimhan, & Kolatkar, 2012). (B) Phylogenic tree of the human SOX family members established based on sequence conservation in the HMG domain. It was generated using the UPGMA method in MacVector software (version 16.0.8). Skeletogenic SOX proteins are highlighted in blue. (C) Schematics of the domain structure of skeletogenic SOX proteins. HMG, DNA-binding domain; TAD, transactivation domain; D, dimerization domain. The same colors are used for the dimerization and transactivation domains of same-group proteins because of high conservation. Different colors are used for these domains for distinct-group proteins to reflect the lack of homology.

Fig. 2

Schematics summarizing current knowledge of the roles of SOX proteins in cell fate determination and differentiation during skeletogenesis. See the main text for detailed information.