4460 • The Journal of Neuroscience, May 9, 2018 • 38(19):4460–4461

Journal Club

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Uncovering the Role of Sox2 in Oligodendroglia

Kristina Kuhbandner1,2 1Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-Universita¨t Erlangen-Nürnberg, Germany, Research Training Group 2162 and 2University Hospital Erlangen IZKF-Doktorandenakademie, Interdisciplinary Center of Neuroscience, ICN School, Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg Review of Zhang et al

In the CNS, oligodendrocytes are re- proliferation and maintenance of neural in the spinal cord may be partially compen- sponsible for the formation of myelin. progenitor properties (Bylund et al., 2003). sated for by Sox3, another member of the To build these insulating sheaths sur- After neuronal differentiation, Sox2 expres- SoxB1 family (Hoffmann et al., 2014). rounding axons, cells of the oligodendro- sion decreases in most neurons. However, Next, the authors selectively knocked cyte lineage must go through an intricate Sox2 expression is maintained in other cells out Sox2 in OPCs, which are characterized and temporally matched sequence of pro- derived from SoxB1-expressing NPCs, in- by the expression of platelet-derived growth liferation, migration, differentiation, and cluding oligodendroglia (Hoffmann et al., factor receptor ␣ (PDGFR␣). This reduced myelination (Michalski and Kothary, 2015). 2014; Dai et al., 2015). Recent studies have the number of OPCs in the subcortical This process is tightly regulated through reported somewhat conflicting results re- white matter and subsequently decreased the interaction of various transcription garding the function of Sox2 in the oligo- oligodendrocyte differentiation and myeli- factors and chromatin regulators (Hernan- dendrocyte lineage. Whereas Hoffmann et nation. This effect most likely results from dez and Casaccia, 2015). For example, Sox8, al. (2014) showed that Sox2 is involved in reduced proliferation of OPCs rather than Sox9, and Sox10, which are members of terminal differentiation of oligodendrocytes an increase in apoptosis. Finally, as the re- the SoxE family of transcription factors, and does not affect oligodendrocyte precur- sults from these stage-specific Sox2 ablation are well established players in the develop- sor cell (OPC) proliferation or migration in experiments imply, the deletion of Sox2 in ment of oligodendrocytes (Weider and the embryonic and perinatal spinal cord, all oligodendrocyte lineage cells severely af- Wegner, 2017). Some studies suggest that Zhao et al. (2015) proposed a role for Sox2 fected brain developmental myelination. Sox2, a member of the SoxB1 family, is in the recruitment of OPCs to demyelinated CNS hypomyelination was evident at the also involved in oligodendrocyte develop- spinal cord lesions (Hoffmann et al., 2014; behavioral level by tremor, ataxia, and mo- ment, but its role is less clearly defined. Zhao et al., 2015). tor impairment and was confirmed at pro- Sox2 is a well characterized transcrip- In a recently published article in The tein and mRNA levels. tion factor best known as one of the four Journal of Neuroscience, Zhang et al. (2018) Using two different demyelination reprogramming factors essential for gen- further addressed the functions of Sox2 approaches, Zhang et al. (2018) went erating induced pluripotent stem cells in myelination and remyelination by using on to show that Sox2 was involved in (Takahashi and Yamanaka, 2006). Origi- several conditional knock-out mouse strains. oligodendrocyte regeneration and re- nally, it was identified as a key factor for In contrast to the findings of Zhao et al. myelination. Specifically, they showed induction and maintenance of pluripo- (2015), Zhang et al. (2018) showed Sox2 ex- that cuprizone-induced demyelination and tency in embryonic and neural stem cells pression not only in early postnatal OPCs, MOG35–55 peptide-induced experimental au- (Graham et al., 2003; Masui et al., 2007). but also in adult OPCs in the brain. Further- toimmune encephalomyelitis (MOG-EAE) Sox2 expression persists in neural progen- more, Sox2 was transiently upregulated in increased the numbers of Sox2 ϩ cells in the itor cells (NPCs), where it regulates the newly differentiated oligodendrocytes. Spe- corpus callosum and spinal cord, respec- cific deletion of Sox2 in mature oligoden- tively. Moreover, conditional ablation of Received Feb. 28, 2018; revised April 5, 2018; accepted April 12, 2018. drocytes revealed reduced oligodendrocyte Sox2 in OPCs resulted in reduced numbers The author declares no competing financial interests. differentiation and myelination in the brain. of newly regenerated oligodendrocytes and Correspondence should be addressed to Kristina Kuhbandner, Depart- Surprisingly, this effect was not seen in post- proliferating OPCs in the corpus callosum ment of Neurology, University Hospital Erlangen, Friedrich-Alexander- natal spinal cord, suggesting that the regula- in the remyelination phase of the cupri- Universita¨t Erlangen-Nu¨rnberg, Schwabachanlage 6, 91054 Erlangen, Germany. E-mail: [email protected]. tion of oligodendrocyte differentiation by zone model. Similarly, Sox2 deletion in DOI:10.1523/JNEUROSCI.0556-18.2018 Sox2 is region-specific. A potential explana- OPCs diminished the density of OPCs, the Copyright © 2018 the authors 0270-6474/18/384460-02$15.00/0 tion for this difference is that the loss of Sox2 number of proliferating OPCs and newly Kuhbandner • Journal Club J. Neurosci., May 9, 2018 • 38(19):4460–4461 • 4461 regenerated oligodendrocytes in the spi- not in the spinal cord. Therefore, the role of SOX2 functions to maintain neural progenitor nal cord after MOG-EAE. Collectively, the Sox2 in oligodendrocyte differentiation in identity. Neuron 39:749–765. CrossRef Medline study by Zhang et al. (2018) demonstrated a this CNS region remains to be specified. He D, Marie C, Zhao C, Kim B, Wang J, Deng Y, region- and time-specific involvement of Sox2 Nevertheless, this hypothetical mechanism Clavairoly A, Frah M, Wang H, He X, Hmidan H, Jones BV, Witte D, Zalc B, Zhou X, Choo in the regulation of OPC proliferation, oligo- is worth further investigation, for example DI, Martin DM, Parras C, Lu QR (2016) dendrocyte differentiation, and myelination. by determining the influence of Sox2 dele- Chd7 cooperates with Sox10 and regulates the There is evidence that Sox2, in addition tion on miRNA145 and its targets during onset of CNS myelination and remyelination. to being a transcriptional regulator, may act development, as well as in demyelinating Nat Neurosci 19:678–689. CrossRef Medline as a pioneer factor that prepares genes on conditions in the brain. Hernandez M, Casaccia P (2015) Interplay be- the epigenetic level for regulation by other Efficient progression of oligodendrocyte tween transcriptional control and chromatin factors (Wegner, 2011). For instance, Zhang lineage cells is vital for the formation of new regulation in the oligodendrocyte lineage. et al. (2018) propose an interaction of Sox2 myelin during development, as well as for Glia 63:1357–1375. CrossRef Medline Hoffmann SA, Hos D, Ku¨spert M, Lang RA, with chromodomain helicase DNA binding remyelination. In some demyelinating dis- Lovell-Badge R, Wegner M, Reiprich S (2014) protein 7 (Chd7), a chromatin-modifying en- orders, such as multiple sclerosis, this process Stem cell factor Sox2 and its close relative Sox3 zyme, previously identified as a transcriptional is severely affected. Yet, no potent treatment have differentiation functions in oligodendrocytes. cofactor of Sox2 in neural stem cells and of that directly enhances repair is available Development 141:39–50. CrossRef Medline Sox10 in oligodendrocyte lineage cells (En- (Plemel et al., 2017). Therefore, to develop Masui S, Nakatake Y, Toyooka Y, Shimosato D, gelen et al., 2011;He et al., 2016). Indeed, the new therapies, it is necessary to gain further Yagi R, Takahashi K, Okochi H, Okuda A, interaction of Sox2 and Chd7 in OPCs was insights into mechanisms preventing demy- Matoba R, Sharov AA, Ko MS, Niwa H recently reported by Doi et al. (2017). That elination and promoting remyelination. (2007) Pluripotency governed by Sox2 via regulation ofOct3/4 expression in mouse embry- study provided evidence for a role of the The work by Zhang et al. (2018), together onic stem cells. Nat Cell Biol 9:625–635. CrossRef Sox2-Chd7 complex in OPC activation and with other previous studies, helps to eluci- Medline identified two proteins—regulator of cell cycle date the function of Sox2 in the complex Michalski JP, Kothary R (2015) Oligodendro- (Rgcc) and protein kinase C␪ (PKC␪)—as regulatory network controlling the gene- cytes in a nutshell. Front Cell Neurosci 9:340. two possible downstream targets (Doi et al., ration of myelinating oligodendrocytes, thus CrossRef Medline 2017). These proteins are involved in the identifying a possible target for regulating Ou WB, Zhu MJ, Demetri GD, Fletcher CD, regulation of cell proliferation in different OPC activation and for fostering functional Fletcher JA (2008) Protein kinase C-theta cell types (Badea et al., 1998; Pfeifhofer et al., recovery in demyelinating diseases. regulates KIT expression and proliferation in gastrointestinal stromal tumors. Oncogene 27: 2003; Ou et al., 2008; Fosbrink et al., 2009). 5624–5634. CrossRef Medline Consistent with this, knockdown of Rgcc References Badea TC, Niculescu FI, Soane L, Shin ML, Rus H Pfeifhofer C, Kofler K, Gruber T, Tabrizi NG, Lutz and PKC␪ in OPC cultures decreased the C, Maly K, Leitges M, Baier G (2003) Protein ϩ ϩ ϩ (1998) Molecular cloning and characteriza- percentage of EdU , Ki67 , PDGFR␣ ,or kinase C theta affects Ca2ϩ mobilization and ϩ tion of RGC-32, a novel gene induced by com- Sox10 cells, indicating their requirement plement activation in oligodendrocytes. J Biol NFAT cell activation in primary mouse T cells. for OPC proliferation (Doi et al., 2017). Chem 273:26977–26981. CrossRef Medline J Exp Med 197:1525–1535. CrossRef Medline However, it is necessary to verify these find- Bylund M, Andersson E, Novitch BG, Muhr J Plemel JR, Liu WQ, Yong VW (2017) Remyeli- ings in vivo and to further test the hypothesis (2003) Vertebrate neurogenesis is counteracted nation therapies: a new direction and challenge by Sox1–3 activity. Nat Neurosci 6:1162–1168. in multiple sclerosis. Nat Rev Drug Discov 16: that Sox2 promotes OPC proliferation via 617–634. CrossRef Medline activation of Rgcc and PKC␪. In this con- CrossRef Medline Dai J, Bercury KK, Ahrendsen JT, Macklin WB Takahashi K, Yamanaka S (2006) Induction of text, it would be reasonable to investigate (2015) Olig1 function is required for oligoden- pluripotent stem cells from mouse embryonic the effect of Sox2 deletion on the expression drocyte differentiation in the mouse brain. and adult fibroblast cultures by defined fac- of these candidate factors in the spinal cord J Neurosci 35:4386–4402. CrossRef Medline tors. Cell 126:663–676. CrossRef Medline and brain at different developmental stages Doi T, Ogata T, Yamauchi J, Sawada Y, Tanaka S, Vogl MR, Reiprich S, Ku¨spert M, Kosian T, Schrewe of oligodendrocyte lineage cells. Moreover, Nagao M (2017) Chd7 collaborates with H, Nave KA, Wegner M (2013) Sox10 cooper- using different conditional genetic mutants Sox2 to regulate activation of oligodendrocyte ates with the mediator subunit 12 during termi- ␪ precursor cells after spinal cord injury. J Neu- nal differentiation of myelinating glia. J Neurosci for Rgcc and PKC in OPCs would provide 33:6679–6690. CrossRef Medline further insight about their role in oligoden- rosci 37:10290–10309. CrossRef Medline Emery B, Agalliu D, Cahoy JD, Watkins TA, Wegner M (2011) SOX after SOX: SOXession reg- drocyte development in vivo. Dugas JC, Mulinyawe SB, Ibrahim A, Ligon ulates neurogenesis. Genes Dev 25:2423–2428. Another way that Sox2 might function in KL, Rowitch DH, Barres BA (2009) Myelin CrossRef Medline OPC differentiation was proposed by Hoff- gene regulatory factor is a critical transcrip- Weider M, Wegner M (2017) SoxE factors: tran- mann et al. (2014). Their study implicated tional regulator required for CNS myelina- scriptional regulators of neural differentiation Sox2 as a potential regulator of microRNAs tion. Cell 138:172–185. CrossRef Medline and nervous system development. Semin Cell (miRNAs) and identified miRNA145 as a Engelen E, Akinci U, Bryne JC, Hou J, Gontan C, Dev Biol 63:35–42. CrossRef Medline Zhang S, Zhu X, Gui X, Croteau C, Song L, Xu J, possible target. Repression of this miRNA Moen M, Szumska D, Kockx C, van Ijcken W, Dekkers DH, Demmers J, Rijkers EJ, Bhat- Wang A, Bannerman P, Guo F (2018) Sox2 results in the activation of several factors in- tacharya S, Philipsen S, Pevny LH, Grosveld is essential for oligodendroglial proliferation volved in oligodendrocyte development and FG, Rottier RJ, Lenhard B, Poot RA (2011) and differentiation during postnatal brain differentiation, such as Myrf (myelin regu- Sox2 cooperates with Chd7 to regulate genes myelination and CNS remyelination. J Neuro- latory factor) and Med12 (Emery et al., that are mutated in human syndromes. Nat sci 38:1802–1820. CrossRef Medline 2009; Vogl et al., 2013; Hoffmann et al., Genet 43:607–611. CrossRef Medline Zhao C, Ma D, Zawadzka M, Fancy SP, Elis- 2014). Loss of Sox2 in OPCs might enhance Fosbrink M, Cudrici C, Tegla CA, Soloviova K, Ito Williams L, Bouvier G, Stockley JH, de Castro miRNA145 levels, thereby inhibiting the T, Vlaicu S, Rus V, Niculescu F, Rus H (2009) GM, Wang B, Jacobs S, Casaccia P, Franklin RJ Response gene to complement 32 is required for (2015) Sox2 sustains recruitment of oligo- translation of these prodifferentiation fac- C5b-9 induced cell cycle activation in endothe- dendrocyte progenitor cells following CNS tors. Interestingly, Zhang et al. (2018) re- lial cells. Exp Mol Pathol 86:87–94. CrossRef demyelination and primes them for differen- ported an effect of Sox2 deletion only on Medline tiation during remyelination. J Neurosci 35: oligodendrocyte differentiation in the brain, Graham V, Khudyakov J, Ellis P, Pevny L (2003) 11482–11499. CrossRef Medline