Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sox2 (SRY-Box 2)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101970

Synonyms

Historical Background

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

The human Sox2 gene is located on chromosome 3q26.33. The structure of the human Sox2 protein is shown in Fig. 1a. The protein contains 317 amino acids and has 80 conserved amino acids of an HMG domain that functions as a DNA-binding domain and for associations with partner proteins. Sox2 also consists of two conserved domains, the N-terminal domain and the C-terminal transactivation domain, which function in activation or repression of transcription. Heterozygous mutations of the Sox2 gene cause anophthalmia–esophageal–genital (AEG) syndrome, which presents with the symptoms of small eyes (microphthalmia), brain-dysfunctional deafness, and tracheoesophageal fistula. The positions of 14 direct stop codon mutations identified in patients are shown in red in Fig. 1a (Kelberman et al. 2006; Williamson et al. 2006). Sox2 functions as a transcription factor that binds to the minor groove of DNA as the consensus motif, as shown by the JASPAR database (Fig. 1b). Sox2 is an architectural transcription factor, and its binding to DNA changes the structure of DNA by causing its sharp bending at 80 to 135° through an HMG domain. This activity enables Sox2 to interact with other nearby partner factors. The transcription of Sox2 mRNA from a single exon can be regulated through both 5′ upstream and 3′ downstream regions, and several such regulatory regions have been identified. These regions, which are well conserved among different species, are called the N-box (N1 to N5) and the Sox2 regulatory region (SRR) 1/2; these are regulated by different signaling factors in a developmental time- and stage-specific manner (Fig. 1d) (Uchikawa et al. 2003; Miyagi et al. 2004). Sox2 is controlled by the partnership with Pou5f1/Octamer-binding transcription factor 3 (Oct3/4) through the positive autoregulation complex on N2 or SRR1 in the 5′ enhancer in ESCs (Boyer et al. 2005). In developing NSCs, two enhancers, N2/SRR1 as the 5′ enhancer and SRR2 as the 3′ enhancer, are critically activated by Sox2 and transcription factors, Pou3f3/Brain-specific homeobox 1 (Brn1) or Pou3f2/Brain-specific homeobox 2 (Brn2) by a positive feedback mechanism (Catena et al. 2004).
Sox2 (SRY-Box 2), Fig. 1

Functional gene structure of Sox2. (a) Domain structure of the human Sox2 protein. The amino acids with numbers shown in red above the protein schema represent the sites of human congenital nonsense mutations causing ocular abnormalities. HMG: high-mobility group. (b) The consensus sequence of the Sox2 binding motif. (c) DNA-bound Sox2 protein. Sox2 protein induces sharp bending of DNA (light blue) through the HMG domain (orange). N-terminal domain and C-terminal activation domain of Sox2 are presented in dark blue and red, respectively. (d) The gene structure of Sox2. Sox2 (coding region and untranslated regions are indicated as gray and black boxes, respectively) is an intron-less single open reading frame gene with conserved sequence blocks, named N1 to N5, in the SRR1 or 2 (SRR: Sox2 regulatory region) 5′ and 3′ untranslated regions, which have enhancer activities in pluripotent stem cells and/or the central nervous system

Expression of the Sox2 Gene

Sox2 is maternally expressed in primitive embryonic cells. Its expression is restricted to the ICM, primitive ectoderm, and several tissue stem/progenitor cells during developmental progression (Fig. 2). The homozygous deletion of Sox2 leads to dysplasia of ICM and causes embryonic lethality in mice (Avilion et al. 2003). Moreover, RNA interference has revealed that the maternal Sox2 protein plays an essential role in the establishment of both ICM and TE (Keramari et al. 2010). Sox2 expression in the primitive ectoderm is localized mainly to the neuroectoderm, as well as parts of the mesoderm, endoderm, and primordial germ cells (PGCs). The restricted high expression of Sox2 promotes specification of the early stage of the neuroectoderm, which produces NSCs by suppressing expression of the Brachyury gene, a mesoendoderm inducer (Thomson et al. 2011). Sox2 expression is localized to NSCs in the ventricular cell layer of the neurocortex during early embryogenesis and becomes restricted to the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampus in the adult brain. In the central and peripheral nervous systems, Sox2 has important roles for controlling the self-renewal, proliferation, and multipotency of NSCs (Pevny and Nicolis 2010). In mesodermal tissue, the osteoblast progenitors partly depend on Sox2 function for the process of differentiation. For example, mice in which the osteoblastic expression of Sox2 is specifically depleted present a phenotype of low bone mass (Basu-Roy et al. 2010). Sox2 also supports the specification and differentiation of endoderm tissue, such as trachea, esophagus, stomach, tracheal cartilage, and lung, during development (Que et al. 2007, 2009; Gontan et al. 2008). Moreover, Sox2 has a critical function in PGC proliferation in the development of embryonic germ cells (Campolo et al. 2013).
Sox2 (SRY-Box 2), Fig. 2

Sox2 expression throughout development. The expression of Sox2 is observed throughout development in restricted regions. Sox2 expression is initially detected in the zygote and continually in the inner cell mass (ICM) of the blastocyst and subsequently in ectoderm, mesoderm, endoderm, and germ cells. The descendants of each tissue contain Sox2-positive stem/progenitor or differentiated cells

The Signaling Pathways of Sox2

Signal inducers, such as Sonic hedgehog (SHH), epidermal growth factor (EGF), insulin-like growth factor (IGF), leukemia inhibitory factor (LIF), and the wingless/int family (WNT), are important regulators of the stemness, proliferation, differentiation, survival, and tumorigenesis of stem cells (Fig. 3). SHH transduces signals into the interior of cells through its receptor Patched, which activates the Smo–Gli signaling pathways. SHH is the one of the stemness regulators for NSCs of the dentate gyrus (DG) in the hippocampus (Palma et al. 2005; Han et al. 2008; Favaro et al. 2009). Interestingly, there is a putative positive feedback system in which Sox2 activates the expression of the Shh gene, and Gli2 regulates the expression of the Sox2 gene (Takanaga et al. 2009). Although the pathway involving EGF and its receptor (EGF–EGFR) contributes to controlling the self-renewal, proliferation, and survival activities of NSCs and the induction of multipotency of NSCs from neural progenitor cells (NPCs) (Doetsch et al. 2002), there is another positive feedback loop between Sox2 and EGFR. Sox2 potentiates the expression of the Egfr gene, and EGFR signaling augments the expression of Sox2 (Hu et al. 2010). IGF is involved in neurogenesis through the ERK and AKT pathway, which controls Sox2 expression in hippocampal NPCs (Peltier et al. 2011). In addition, LIF activates the Jak–Stat3 signaling pathway and has an essential role in the pluripotency of mouse ESCs. LIF–Jak–Stat3 signaling activates Sox2 through Klf4 transactivation (Niwa et al. 2009). WNT is a ligand for the Frizzled receptor, and the ligand–receptor signal transduction inhibits the phosphorylation of β-catenin by a Ser/Thr kinase, GSK3β. The stabilized β-catenin protein is then translocated into the nucleus as a transcription factor. The WNT and β-catenin signaling pathway supports LIF signaling by stimulating Stat3 transcription to maintain pluripotency and occlude the differentiation of mouse ESCs (Hao et al. 2006). While the WNT and β-catenin signaling pathway activates the proliferation and progression of neurogenesis for NSCs in SVZ and SGZ, Sox2 competes with and antagonizes β-catenin on the same binding site on the promoters of target genes in adult NSCs (Kuwabara et al. 2009).
Sox2 (SRY-Box 2), Fig. 3

Extracellular signal inducers and output cellular functions of Sox2. The extracellular signaling molecules induce several intracellular outputs through Sox2. LIF leukemia inhibitory factor, WNT wingless/int family, SHH Sonic hedgehog, EGF epidermal growth factor, IGF insulin-like growth factor

The Direct Downstream Factors of Sox2

Sox2 acts as a transcription factor to directly regulate many target genes (Fig. 4). For example, the expression of Sox2 has crucial roles in NSCs and ESCs. In NSCs, the neural stem cell marker gene Nestin is regulated by Sox2 and Brn1/2 (Josephson et al. 1998; Tanaka et al. 2004). Although the EGF–EGFR signaling pathway that stimulates Sox2 expression is an important regulator of the proliferation and acquisition of multipotency of NSCs, Sox2 also regulates the expression of EGFR (Hu et al. 2010). In addition, Sox2 drives Shh gene expression to control the stemness of hippocampal NSCs (Favaro et al. 2009). Under this signaling pathway, the transcription factor Gli2 activates Sox2 gene expression (Takanaga et al. 2009). Sox2 also regulates the transcription of nuclear receptor Tlx/Nr2e1, which is indispensable for the maintenance of stemness of NSCs through direct molecular association (Shimozaki et al. 2012). In ESCs, Sox2 has both direct and indirect regulatory effects on the transcription of a POU factor, Oct4, which is a transcription factor that is essential for the maintenance of undifferentiated ESCs. The specific partner complex between Sox2 and Oct4 can be directly activated by these components themselves via autoregulatory transcriptional regulation in ES cells (Sarkar and Hochedlinger 2013). Meanwhile, Sox2 influences Oct4 expression indirectly through the expression of the nuclear receptor Nr5a2, which is a regulator of Oct4 transactivation (Masui et al. 2007). In addition, Sox2 regulates the transcription factor Nanog, which is associated with maintenance of the self-renewal and pluripotency of ES cells, with Oct4 also acting as an essential partner; this also involves transcriptional regulation of the Utf1 and Fgf4 genes (Niwa 2001). The Sox2 and Oct4 complex also targets developmental pluripotency associated 4 (Dppa4) in ES cells. Dppa4 is involved in the epigenetic regulation of chromatin for the pluripotency of ES cells to prevent the differentiation into cells with a primitive ectoderm cell fate (Chakravarthy et al. 2008). Although the transcription factor Brachyury drives mesodermal differentiation, Sox2 suppresses Brachyury gene expression by directly binding to its promoter in ES cells (Thomson et al. 2011). This suggests that the process of specification that determines the fate of cells as either neuroectoderm or mesoderm occurs during embryogenesis.
Sox2 (SRY-Box 2), Fig. 4

Direct targets of Sox2 in NSCs and ESCs. The genes shown in green or orange are directly regulated by Sox2 in neural stem cells (NSCs) and embryonic stem cells (ESCs), respectively

Partnership of Sox2 and Stem Cell Reprogramming

Sox2 has a specific partnership with a protein family that has a conserved homeodomain, and Sox2 associates with this family through the HMG domain. The partner complex between Sox2 and this family including POU factors controls the maintenance of an undifferentiated state in ESCs and NSCs by regulating self-renewal and antidifferentiation processes. Although Sox2 and Oct4 form a specific partner complex in ESCs and regulate the transcription of target genes (Niwa 2001), the partner relationship between Sox2 and the homeodomain protein family could also produce a variety of stem cell characteristics (Kondoh and Kamachi 2010). As shown in Fig. 5a, homeodomain proteins such as paired box gene 6 (Pax6), Brn2, and paired related homeobox 1 (Prx1/Prrx1) are associated with the regulation of NSCs. For example, the Sox2–Pax6 complex regulates a specific type of NSCs involved in neurogenesis of the optic nerve and lens cells (Kamachi et al. 2001; Inoue et al. 2007) and that of hippocampal DG cells in the adult brain (Maekawa et al. 2005). Although Nestin is a component of intermediate filaments and a marker of NSCs, Sox2 and Brn1/2 cooperate to regulate expression of the Nestin gene (Josephson et al. 1998; Tanaka et al. 2004). Furthermore, the synergistic activation between Sox2 and Prx1 serves as a form of partner regulation of the stemness of adult NSCs (Shimozaki et al. 2013). Therefore, it is supposed that the relationship between Sox2 and the homeodomain protein family plays a fundamental role as the key molecular switch regulating stem cells.
Sox2 (SRY-Box 2), Fig. 5

Partners of Sox2 and direct stem cell reprogramming. (a) Partnership between Sox2 and homeodomain factors in ESCs and NSCs. (b) Sox2 and homeodomain factors play a critical role in stem cell reprogramming by the transactivation of defined genes. iPSCs induced pluripotent stem cells, iN/iNSCs induced neuronal or induced neural stem cells

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.

Summary

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.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Functional Genomics, Life Science Support CenterNagasaki UniversityNagasakiJapan