Sox2 (SRY-Box 2)
The sex-determining region Y (SRY/Sry) gene, which is a mammalian male-specifying factor on the Y chromosome, was first defined in 1990. Since its discovery, more than 20 different Sry-related genes that have high-mobility group (HMG) box sequences similar to Sry have been cloned, and they form the conserved Sry-related HMG box (SOX) gene family. These genes are classified into subgroups based on the HMG box domain structure and other protein characteristics. The members of the SoxB1 group gene family, called Sox1, Sox2, and Sox3, were found to exhibit highly tissue-specific expression during mouse embryogenesis (Bowles et al. 2000). They show similar expression patterns in embryos, and are functionally redundant, with more than 80% amino acid sequence similarity. Sox2 is indispensable during the development of a wide range of species. It targets several genes with diverse biological effects via the association of cofactors. The function of Sox2 as a transcriptional activator or repressor was revealed upon its combination with its partner factors, which is referred to as the SOX-partner code theory (Kondoh and Kamachi 2009). Sox2 has been confirmed to be expressed in mouse embryogenesis during the morula, inner cell mass (ICM) of blastocyst, epiblast, and neuroectoderm stages. Mice having a zygotic null homozygous mutation of Sox2 showed embryonic lethality around the implantation period (Avilion et al. 2003). In addition, the maternal/zygotic disruption of Sox2 mRNA by RNA interference showed the indispensability of Sox2 functions during early embryogenesis, especially at the ICM and trophectoderm (TE) stages (Keramari et al. 2010). Sox2 also has important roles in later developmental stages, especially in neural stem cells (NSCs). The dominant-negative form of Sox2 inhibits the maintenance of stemness and the neuronal differentiation of NSCs (Graham et al. 2003). Studies using mutant mice with hypomorphic alleles or the combination of a null allele and 5′ enhancer-specific inactivation of Sox2 have also demonstrated the importance of Sox2 for the neuronal regulation of NSCs in the retina and forebrain (Ferri et al. 2004; Taranova et al. 2006). Sox2 is also critically important for the stemness of NSCs and embryonic stem cells (ESCs), which can be established in vitro from ICM by appropriate culturing. Furthermore, technologies for the artificial induction of pluri- or multipotent stem cells have recently been developed by defined gene transactivation with Sox2.
Structure of the Sox2 Gene
Expression of the Sox2 Gene
The Signaling Pathways of Sox2
The Direct Downstream Factors of Sox2
Partnership of Sox2 and Stem Cell Reprogramming
Recently, direct reprogramming technology has been developed using a defined combinational gene-transfection system. As shown in Fig. 5b, Sox2 is considered to play a central role in reprogramming by partnering with homeodomain factors. Sox2 can induce somatic cells to become pluripotent stem cells by transactivation of the Oct4, Klf4, and c-Myc genes (Takahashi and Yamanaka 2006). The combinational forced expression of Sox2 with Brn2, Ascl1, and Myt1l genes also represents a direct conversion from somatic fibroblasts into differentiated neurons called iN cells (Vierbuchen et al. 2010). Interestingly, Sox2 alone can directly reprogram fibroblasts into cells that have the characteristics of NSCs, called iNSCs, under specific culture conditions and more than 40 days of culture (Ring et al. 2012). Sox2 acting alone may have the potential to produce an intracellular environment in which induction of gene expression of homeodomain factors occurs, for direct stem cell reprogramming.
Sox2 is a transcription factor and a member of the HMG domain-containing protein family, which is essential for maintaining the stemness of stem cells. The conserved HMG region has specific roles in both DNA binding to a consensus motif and the association with partner proteins having a specific relationship with stem cell regulation. The Sox2 gene is controlled through its 5′- and/or 3′-UTR by POU factors, such as Oct4 and Brn1/2, which partner with Sox2 in a positive feedback system. The maternal expression of Sox2 is critical at an early stage of embryogenesis and plays a key role in the establishment of both ICM and TE. During development, Sox2 expression becomes localized at the neurectoderm and promotes cell-fate specification by suppressing mesoendoderm inducers. In a restricted region of the adult brain, Sox2 confers NSCs with the capacities for self-renewal and multipotent differentiation. In addition, some Sox2 expression is also presented in the stem/progenitor cells in the mesoderm, endoderm, and PGCs. Sox2 also plays a functional role in the proliferation of those cells. Extracellular signaling molecules, such as SHH, EGF, IGF, LIF, and WNT, have important regulatory effects for stemness, proliferation, differentiation, survival, and tumorigenesis of stem cells by controlling Sox2 expression. Sox2 directly targets genes that are critical for maintenance of the stemness of NSCs or ESCs. In the regulation of Sox2, the specific partnership between Sox2 and the homeodomain protein family is a key molecular switch for the cellular function of stem cells. Moreover, although recent gene transactivation technology has enabled the direct reprogramming of somatic cells into stem cells, Sox2 plays a central role in this process. However, the molecular and cellular mechanisms behind Sox2 function still remain to be elucidated. Further research should lead to a deeper understanding of its basic molecular biological functions and reveal ways in which the Sox2 gene can be targeted in a clinical context.