Regulation of the SOX 3 Gene

SOX3 gene expression by retinoic acid 2 Summary Sox3/SOX3 gene is considered to be one of the earliest neural markers in vertebrates. Despite the mounting evidence that Sox3/SOX3 is one of the key players in the development of the nervous system, limited data are available regarding the transcriptional regulation of its expression. This review is focused on the retinoic acid induced regulation of SOX3 gene expression, with particular emphasis on the involvement of retinoid receptors. Experiments with human embryonal carcinoma cells identified two response elements involved in retinoic acid/retinoid X receptor-dependent activation of the SOX3 gene expression: distal atypical retinoic acid-response element, consisting of two unique G-rich boxes separated by 49 bp, and proximal element comprising DR-3-like motif, composed of two imperfect hexameric half-sites. Importantly, the retinoic acid-induced SOX3 gene expression could be significantly down-regulated by a synthetic antagonist of retinoid receptors. This cell model provides a solid base for further studies on mechanism(s) underlying regulation of expression of SOX3 gene, which could improve the understanding of molecular signals that induce neurogenesis in the stem/progenitor cells both during development and in adulthood. The Sox/SOX gene family encodes transcription factors that act as key regulators of diverse developmental processes, such as early embryogenesis, gastrulation, neural induction, formation of various organs and tissues, specification and differentiation of many cell types (Lefebvre et al. 2007, Pevny and Lovell-Badge 1997, Wegner 1999). It is known that SOX transcription factors carry a DNA-binding HMG domain and perform their functions in complex interplay with other transcription factors in a manner highly dependent on cell type and promoter context (Kamachi et al. 2000). They show both classical and architectural modes of action (Pevny and Lovell-Badge 1997), either activating or repressing specific target genes (Wilson and Koopman 2002). Based on protein sequence comparisons, Sox/SOX transcription factors are divided into 10 distinct groups designated A-J (Bowles et al. 2000). SOX3 together with SOX1 and SOX2 belongs to the SOXB1 subgroup of transcriptional activators (Uchikawa et al. 1999), which are pan-neurally expressed and have redundant roles in maintaining the broad developmental potential and identity of neural stem cells (Bylund et al. 2003, Pevny and Placzek 2005). In addition to regulating progression of neurogenesis, this group of activators is also operative in post-mitotic neurons (Ekonomou et al. 2005, Ferri et al. 2004, Rizzoti et al. 2004). Sox3/SOX3 gene is an X-linked member of the family and the closest relative of sex-determining …