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Sox2 Signaling Pathway


Figure 1. Sox2 signaling pathway. Red letters indicate that Sox2 promotes the expression of those genes while the green letters indicate the opposite. The location of the N1 to N5 enhancers are indicated. TSS and TTS represent transcription starting and termination sites, respectively

An overview of Sox2

Sox2 (sex-determining region Y (SRY)-box 2) is a transcriptional factor which is essential for maintaining self-renewal/proliferation/pluripotency of undifferentiated embryonic stem cells (ESCs) and multipotency of neural stem cells (NSCs). Sox2 is a member of the Sox family of transcription factors. The Sox gene family was first defined by the discovery of the mammalian testis-determining factor, Sry. Proteins of the Sox family all share a highly conserved high-mobility-group (HMG) DNA binding domain with more than 80% sequence identity. Sox2 is classified as a member of SoxB1 group, which also includes Sox1 and Sox3.

Like other transcription factors, the expression of Sox2 is regulated by both intrinsic factors and extrinsic signaling pathways. In ESCs, Oct4, Nanog, mothers against decapentaplegic homolog 1/3 (Smad1/3) and signal transducer and activator of transcription 3 (Stat3) are identified to be involved in the formation of the autoregulatory complex in mESCs, which activate Sox2 as well as other pluripotent genes. In NPCs, Sox2 expression is promoted by transcriptional factors such as activating protein 2 (AP-2), prospero homeobox protein 1 (Prox1) and Pax6. E2f3a cooperates with the pRb family member p107 to repress Sox2 expression, whereas E2f3b activates Sox2 expression by recruiting RNA polymerase II to its promoter. Cyclin-dependent kinase inhibitor p21 has also been found to directly bind to a Sox2 enhancer and repress Sox2 expression in NPCs. Besides, T3/TRα1 (Thyroid Hormone and its receptor, TRα1) directly represses Sox2 expression in the adult SVZ (subventricular zone). Acetylation of Sox2 by histone acetyltransferase, p300, induces its nuclear export in ESCs, leading to increased ubiquitination and proteasomal degradation of Sox2 protein.

Functions of Sox2

As a component of the core transcriptional regulatory network which maintains the totipotency of the cells during embryonic preimplantation period, the pluripotency of embryonic stem cells, and the multipotency of neural stem cells, Sox2 takes part in various number of developmental processes.

Sox2 with stem cell pluripotency

The cytokine leukaemia inhibitory factor (LIF) integrates signals into mouse embryonic stem (ES) cells to maintain pluripotency. The two LIF signalling pathways, Jak–Stat and PI3K–Akt pathways, are each connected to the core circuitry via different transcription factors. The Jak–Stat3 pathway activates Klf4, whereas the PI3K–Akt pathway stimulates the transcription of Tbx3. The MAPK pathway antagonizes the nuclear localization of Tbx3. Klf4 and Tbx3 mainly activate Sox2 and Nanog, respectively, and maintain the expression of Oct4. Transcription of all these transcription factors is positively regulated by Oct4, Sox2 and Nanog, which may confer robustness and stable expression in the absence of all signals.

Oct4, Sox2, and Nanog contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. Among these active genes, several encoding transcription factors (e.g., Oct4, Sox2, Nanog, Stat3, Zic3) and components of the TGF-β (e.g., Tdgf1, Lefty2/Ebaf) and Wnt (e.g., Dkk1, Frat2) signaling pathways are notable targets. Among transcriptionally inactive genes, there are genes that specify transcription factors important for differentiation into extra-embryonic, endodermal, mesodermal, and ectodermal lineages (e.g., Esx1l, Hoxb1, Meis1, Pax6, Lhx5, Lbx1, Myf5, Onecut1).

Sox2 with neural progenitor/stem cells

In neural progenitors, Sox2 is shown to interact with the transcription factor Brn2 to activate the NPC-associated Nestin gene expression. During lens development, Pax6 and Sox2 combine to activate the δ-crystallin gene and induce lens placode formation by binding to lens-specific enhancer elements. Sox2 is required for maintaining endogenous levels of Lin28 in NPCs, which can regulate let-7 miR biogenesis that has recently been implicated in global modulation of mRNA splicing. It has been reported that Sox2 is able to interact with long non-coding RNA rhabdomyosarcoma 2-associated transcript (RMST) to co-regulate a large pool of downstream genes in the regulation of neural stem cell fate. The list of genes co-activated by both RMST and Sox2 includes Ascl1, Neurog2, Hey2, and Dlx1, which are neurogenic genes, supporting the roles of RMST and Sox2 in neurogenesis. Chd7, a chromatin remodeling ATPase associated with CHARGE syndrome, is identified as a Sox2 transcriptional cofactor. They cooperatively activate target genes involved in NSCs identity and maintenance, such as Mycn, Gli2, Gli3 and Jag1.

Sox2 with cell fate

Sox2 often determines cell fate by antagonizing transcription factors of alternative cell lineages. Antagonism exists between Sox2 and Tbx6 during the specification of bipotential axial stem cells towards either Sox2+ neural tube or Tbx6+ axial mesoderm. Sox2 antagonizes the transcription factor Nkx2-1 during foregut development; Sox2 is expressed first in the future esophagus and stomach whereas Nkx2-1 is expressed ventrally in the future trachea. The interaction between Sox2 and Mitf/Egr2 regulates the differentiation of Schwann cell progenitors into either myelinating Schwann cells or melanocytes. Specifically, Sox2 maintains the Schwann cell progenitor state whereas its cross-regulatory interactions with either Mitf or Egr2 consolidates mature Schwann cell or melanocyte fates, respectively.

Implications in disease

Sox2 mutations have been identified in a number of developmental diseases and cancers. People with Sox2 heterozygous develop Anophthalmia-Esophageal-Genital Syndrome (AEG). Sox2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cells, and it is demonstrated that Sox2 is a lineage-survival oncogene in lung and esophageal squamous cell carcinoma. Lastly, Sox2 has been shown to be critical for the proliferation and differentiation of human osteosarcoma cell lines in in vitro and in vivo transplantation models by antagonizing Wnt signaling. Sox2 expression has also been suggested to contribute to cellular invasion in tumors of neurological and neural crest origin such as glioma, melanoma, and Merkel cell carcinoma, where it is overexpressed.

References:

1. Zhang S, Cui W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World Journal of Stem Cells. 2014, 6(3):305-311.
2. Niwa H, et al. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. 2009, 460(7251):118-22.
3. Boyer LA, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005, 122(6):947-956.
4. LópezJuárez, et al. Thyroid Hormone signaling acts as a neurogenic switch by repressing Sox2 in the adult neural stem cell niche. Cell Stem Cell. 2012, 10(5):531-543.
5. Feng R, Wen J. Overview of the roles of Sox2 in stem cell and development. Biological Chemistry. 2015, 396(8):883-891.
6. Ng S Y, et al. The long noncoding RNA RMST, interacts with SOX2 to regulate neurogenesis. Molecular Cell. 2013, 51(3):349-359.
7. Engelen E, et al. Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nature Genetics. 2011, 43(6):607-11.
8. Bass A J, et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nature Genetics. 2009, 41(11):1238.
9. Adameyko I, et al. Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest. Development. 2012, 139(2):397-410.
10. Hiroaki Ikushima, et al. Autocrine TGF-β signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell. 2009, 5(5):504-514.
11. Laga A C, et al. Expression of the embryonic stem cell transcription factor SOX2 in human skin : Relevance to melanocyte and merkel cell biology. American Journal of Pathology. 2010, 176(2):903-913.

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