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Sox2, a Key Factor in the Regulation of Pluripotency and Neural Differentiation

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Sox2, a Key Factor in the Regulation of Pluripotency and Neural Differentiation Submit a Manuscript: http://www.wjgnet.com/esps/ World J Stem Cells 2014 July 26; 6(3): 305-311 Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1948-0210 (online) DOI: 10.4252/wjsc.v6.i3.305 © 2014 Baishideng Publishing Group Inc. All rights reserved. TOPIC HIGHLIGHT WJSC 6th Anniversary Special Issues (3): Embryonic stem cells Sox2, a key factor in the regulation of pluripotency and neural differentiation Shuchen Zhang, Wei Cui Shuchen Zhang, Wei Cui, Institute of Reproductive and Devel- gramming opmental Biology, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Campus, Core tip: Sex determining region Y-box 2 (Sox2) plays London W12 0NN, United Kingdom important roles in pluripotent stem cells, not only for Author contributions: Zhang S and Cui W wrote the manu- maintaining their pluripotency but also for directing script. their neural differentiation. There have been many Correspondence to: Wei Cui, PhD, Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, intensive studies in the last decade, which serve to as- Faculty of Medicine, Imperial College London, Hammersmith certain the function of Sox2 in these processes. In this Campus, Du Cane Road, London W12 0NN, review, we have summarized the recent progress made United Kingdom. [email protected] regarding the involvement of Sox2 in pluripotency, Telephone: +44-20-75942124 somatic cell reprogramming and neural differentiation Received: November 28, 2013 Revised: April 7, 2014 as well as the molecular mechanisms underlying these Accepted: May 16, 2014 roles. Published online: July 26, 2014 Zhang S, Cui W. Sox2, a key factor in the regulation of plu- ripotency and neural differentiation. World J Stem Cells Abstract 2014; 6(3): 305-311 Available from: URL: http://www.wjg- Sex determining region Y-box 2 (Sox2), a member of net.com/1948-0210/full/v6/i3/305.htm DOI: http://dx.doi. the SoxB1 transcription factor family, is an important org/10.4252/wjsc.v6.i3.305 transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. Furthermore, INTRODUCTION Sox2 plays an essential role in somatic cell reprogram- Human pluripotent stem cells (hPSCs), including human ming, reversing the epigenetic configuration of differ- embryonic stem cells (hESCs) and induced pluripotent entiated cells back to a pluripotent embryonic state. In stem cells (iPSCs), possess two important properties: in- addition to its role in regulation of pluripotency, Sox2 definite self-renewal in culture and the ability to generate is also a critical factor for directing the differentiation most, if not all, cell types in the human body via differ- of PSCs to neural progenitors and for maintaining the [1,2] properties of neural progenitor stem cells. Here, we entiation into one of the three embryonic germ layers . review recent findings concerning the involvement of These unique properties of hPSCs make them an invalu- Sox2 in pluripotency, somatic cell reprogramming and able cell resource not only for regenerative medicine, neural differentiation as well as the molecular mecha- disease modelling and drug development, but also for nisms underlying these roles. the study of early human development, serving as a cell model to elucidate the molecular mechanisms regulating © 2014 Baishideng Publishing Group Inc. All rights reserved. embryonic cell proliferation and differentiation. Under- standing the mechanisms underlying the self-renewal Key words: Sex determining region Y-box 2; Pluripotent and differentiation of hPSCs is fundamentally important stem cells; Pluripotency; Neural differentiation; Repro- for the subsequent utilization of these cells. In the past WJSC|www.wjgnet.com 305 July 26, 2014|Volume 6|Issue 3| Zhang S et al . Sox2 in pluripotency and neural differentiation decade, increasing evidence has shown that cell fate de- expression is initially detected in cells at the morula stage, termination of a pluripotent stem cell, either maintain- becoming more specifically located in the ICM of blasto- ing pluripotency or differentiating into one of the three cyst and epiblast[12] during the latter stages. This implies germ layers, is controlled by both extrinsic and intrinsic that Sox2 may have important roles in the formation of factors[3]. Intrinsic factors refer mainly to transcription early pluripotent embryonic cells. Indeed, zygotic deletion factors that play an essential role in the direct control of of Sox2 is embryonically lethal due to the failure to form gene expression in cells, while extrinsic factors, includ- pluripotent epiblast whilst the absence of Sox2 has little ing growth factors, extracellular matrices and cytokines, effect on the formation of trophectoderm[12]. Therefore, have considerable effects on expression levels of intrinsic Sox2 is an essential factor in the formation of pluripotent transcription factors through various signalling pathways. cells in early embryos and ultimately an critical factor for The core intrinsic factors for regulating pluripotency embryonic development. have been identified as octamer-binding transcription factor 4 (Oct4), sex determining region Y-box 2 (Sox2) and Nanog[4,5], while Oct4 and Sox2 are also proposed as CRITICAL ROLE OF SOX2 IN lineage specifiers to regulate mesendoderm and ectoderm MAINTAINING PLURIPOTENCY OF ESCS differentiation, respectively[6,7]. Thus, Sox2 is one of the critical factors that control both pluripotency and neural AND GENERATION OF IPSCS differentiation of hPSCs. ESCs, derived from the ICM of preimplantation em- In this review, we place particular emphasis on the bi- bryos, share many characteristics with the ICM cells. ological functions of Sox2 in regulating pluripotency and One major similarity is their pluripotent capability, be- early neural differentiation of ESCs and summarize the ing able to give rise to all cell types of the adult body. recent findings on the role that Sox2 plays in the regula- However, ESCs are not identical to the cells in the ICM tion of PSC fate. as ESCs are able to amplify themselves during extended culture without compromising their pluripotency. Con- SOX2 IS INDISPENSIBLE DURING EARLY sistent with the data in pre-implantation embryos, Sox2 is highly expressed in ESCs. Depletion of Sox2 by ei- EMBRYONIC DEVELOPMENT ther gene-knockout or RNA interference considerably Sox2 is a member of the Sox family of transcription fac- compromises the pluripotent state of both mouse and tors. The Sox gene family was first defined by the discov- human ESCs as shown by the changes in cell morphol- [8,9] ogy, loss of pluripotent marker expression and their dif- ery of the mammalian testis-determining factor, Sry . [2,13] Proteins of the Sox family all share a highly conserved ferentiation primarily into trophectoderm . However, high-mobility-group (HMG) DNA binding domain. forced expression of Oct4 in Sox2-null mouse ESCs To date, 20 different Sox genes have been identified in (mESCs) can rescue the pluripotency of these cells, mouse and human[10], which are divided into subgroups, indicating that the role of Sox2 in maintaining the plu- ripotent state of ESCs is primarily to sustain a sufficient according to the degree of homology within the HMG [2,13] domain and other structural motifs. Sox2 is classified as a level of Oct4 expression . Collectively, these results member of SoxB1 group, which also includes Sox1 and demonstrate that Sox2 is crucial in the maintenance Sox3. Although Sox1, Sox2 and Sox3 share more than of pluripotent ESCs, possibly through promoting and 80% sequence similarity and are functionally redundant, maintaining Oct4 expression. Sox2 can exert distinct functions in a biologically context- Interestingly, to maintain pluripotency of stem cells, dependent manner and is indispensable for embryonic levels of Sox2 expression need to be stringently regu- development. Many factors have been shown to influence lated, with either higher or lower Sox2 expression leading binding of Sox proteins to their target genes, leading to to the loss of pluripotency in ESCs. This could be at- diverse functional effects. One such factor is the interac- tributed to the fact that both low and high levels of Sox2 tion between Sox proteins and various cofactors. Interac- reduce the promoter/enhancer activity of Sox2-Oct4 tar- [14,15] tion with various cofactors confers upon Sox2 greater get genes . The expression level of Sox2 needs to be functional versatility during developmental processes[11]. retained in a dynamic equilibrium with other synergistic During mouse embryogenesis, a totipotent zygote factors in order to maintain pluripotency. This concept is undergoes cleavage to increase the cell number and the also supported by the finding that Sox2 cooperates with resulting multi-cellular morula further develops to form other highly dose-dependent transcription factors, such [4] the blastocyst, in which the cells, for the first time, appear as Oct4 and Nanog, in the regulation of pluripotency . to acquire spatially derived identities, segregating into the In human and mouse ESCs, Oct4, Sox2 and Nanog form inner cell mass (ICM) and trophectoderm. Cells in the a core transcriptional regulatory circuitry in pluripotent ICM give rise to the embryo proper, differentiating into stem cells to maintain their self-renewal. Oct4 and Sox2 all cell types found within the body and are thus classi- co-occupy a large number of enhancers/promoters and fied as pluripotent. Conversely, trophoblast cells develop regulate the expression levels of their target genes (Figure into placental tissues, assisting with implantation and 1). They activate the expression of pluripotent genes, in- nourishment of the embryo during development. Sox2 cluding Nanog and themselves, whilst repressing the ex- WJSC|www.wjgnet.com 306 July 26, 2014|Volume 6|Issue 3| Zhang S et al . Sox2 in pluripotency and neural differentiation P300 Stat3 Smad1/3 RMST E.g., Sox2, Oct4, E.g. , Sox2, Pax6, Oct4 Sox2 Nanog Chd7 Sox2 NTF Nanog, etc . Nestin, SHH, etc . Pluripotency genes Neural progenitor genes P300 Stat3 Smad1/3 RMST E.g.
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