Sox proteins: regulators of cell fate specification and differentiation

Abstract

SummarySox transcription factors play widespread roles during development; however, their versatile functions have a relatively simple basis: the binding of a Sox protein alone to DNA does not elicit transcriptional activation or repression, but requires binding of a partner transcription factor to an adjacent site on the DNA. Thus, the activity of a Sox protein is dependent upon the identity of its partner factor and the context of the DNA sequence to which it binds. In this Primer, we provide an mechanistic overview of how Sox family proteins function, as a paradigm for transcriptional regulation of development involving multi-transcription factor complexes, and we discuss how Sox factors can thus regulate diverse processes during development. Key words: HMG domain, Partner factors, Transcriptional regulation, Stem cells, Cell lineage specification IntroductionAn emerging view of transcriptional regulation in developmental processes is that transcription factor complexes, rather than single transcription factors, play a major role (Reményi et al., 2004;Verger and Duterque-Coquillaud, 2002). This idea has been pioneered, most rigorously tested and studied in a variety of developmental contexts in the case of Sox (SRY-related HMG-box) family proteins. Sox family proteins are a conserved group of transcriptional regulators (see Box 1) defined by the presence of a highly conserved highmobility group (HMG) domain that mediates DNA binding. This domain was first identified in Sry, a crucial factor involved in mammalian male sex determination (Gubbay et al., 1990;Sinclair et al., 1990). Multiple other Sox proteins have subsequently been identified and analysed. Vertebrate genomes contain ~20 Sox family members with highly divergent developmental functions, as was indicated by the initial analyses of Sox expression in embryos (Collignon et al., 1996;Uwanogho et al., 1995). Although Sox proteins are also conserved in invertebrate lineages and exert analogous regulatory functions (Phochanukul and Russell, 2010), we here confine our discussion to the vertebrate Sox family members. In this Primer, we first outline the structure and molecular activities of Sox proteins, before discussing their roles during vertebrate development. In particular, the action and function of Sox proteins will be overviewed as a paradigm for transcriptional regulation mediated by a family of transcription factors. Sox protein structureSox proteins can bind to ATTGTT or related sequence motifs through their HMG domain, which consists of three α helices (Badis et al., 2009;Kondoh and Kamachi, 2010). This binding is established by the interaction of the HMG domain with the minor groove of the DNA, which widens the minor groove and causes DNA to bend towards the major groove (Reményi et al., 2003). It is speculated that DNA bending itself may contribute to the regulatory functions of Sox proteins (Pevny and Lovell-Badge, 1997), but this has not been proved experimentally. Sox proteins are classified into groups A-H, depending on the amino acid sequ...

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

“…SOX proteins are an evolutionarily ancient family of complex-forming transcriptional activators and repressors that are identified by a conserved HMG DNA-binding domain [26,27]. A plethora of SOX genes has been demonstrated to be expressed within the developing pancreas, including most of the C, D, E, F, G and H subfamily members [28].…”

Biomarkers in Malignant Melanoma: Recent Trends and Critical Perspective

“…Among progenitor cell markers of interest are also SOX (Sry-related HMG-Box gene) proteins. Some represent nuclear transcription factors in the differentiation of neural crest progenitor cells to melanocytes, while others are more versatile regulators of stem and progenitor cell fate (72,73). The immunohistochemical profile of SOX10 was used to detect metastatic melanoma in sentinel lymph nodes with high sensitivity and specificity and is supposed to be a reliable marker for supplementing other immunohistochemical stains, like S100B or melan-A (74).…”

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

“…Though the ChIP-seq data we used did not list ASCL1 as an experimentally determined target, literature review has revealed that FOXP2 strongly represses ASCL1 [74]. Additionally, the joint regulation of the common target SOX21 by miR-3666 and FOXP2 maintains the balance of SOX2 and SOX21 activities that, in turn, is required for the balance of progenitor cell maintenance and the progression to postmitotic neural development [75,76].…”