SoxE factors: Transcriptional regulators of neural differentiation and nervous system development

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Review

SoxE factors: Transcriptional regulators of neural differentiation and nervous system development Matthias Weider, Michael Wegner ∗ Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany

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Article history: Received 10 May 2016 Received in revised form 16 August 2016 Accepted 18 August 2016 Available online xxx Keywords: Neural crest Brain Schwann cell Oligodendrocyte Glia Transcriptional network

a b s t r a c t Sox8, Sox9 and Sox10 represent the three vertebrate members of the SoxE subclass of high-mobilitygroup domain containing Sox transcription factors. They play important roles in the peripheral and central nervous systems as regulators of stemness, specification, survival, lineage progression, glial differentiation and homeostasis. Functions are frequently overlapping, but sometimes antagonistic. SoxE proteins dynamically interact with transcriptional regulators, chromatin changing complexes and components of the transcriptional machinery. By establishing regulatory circuits with other transcription factors and microRNAs, SoxE proteins perform divergent functions in several cell lineages of the vertebrate nervous system, and at different developmental stages in the same cell lineage. The underlying molecular mechanisms are the topic of this review. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 SoxE proteins and PNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 SoxE proteins and CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction The SoxE group is a subclass of the Sox family of transcription factors whose members are characterized by a sequence-specific DNA-binding high mobility group (HMG) domain first found in the mammalian sex determining gene Sry [1]. In most verte-

Abbreviations: CNS, central nervous system; C-terminus, carboxyterminus; Hdac, histone deacetylase; HMG, high mobility group; N-terminus, aminoterminus; NC, neural crest; OPC, oligodendrocyte precursor; pMN, precursor to motor neuron; PNS, peripheral nervous system; PCWH, peripheral neuropathy, central dysmyelination, Waardenburg syndrome, Hirschsprung disease; PWH, peripheral neuropathy, Waardenburg syndrome, Hirschsprung disease; SC, Schwann cell; Sry, Sex-determining region on Y chromosome. ∗ Corresponding author at: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054, Erlangen. E-mail address: [email protected] (M. Wegner).

brates, the SoxE group has three members, Sox8, Sox9 and Sox10, whereas invertebrates usually have a single SoxE protein [2]. Sequence conservation among SoxE proteins is much higher than with other Sox proteins, and particularly prominent in functionally relevant domains that comprise from N- to C-terminus a dimerization domain, the HMG domain, a central protein interaction domain (named K2) [3,4] and the C-terminal transactivation domain (Fig. 1A). Although SoxE proteins are not confined to a single cell-type or tissue, they exhibit restricted expression patterns and serve essential functions in a limited number of developmental processes and adult tissues [1,2]. This review will be mainly about SoxE proteins in the nervous system. As functions and mechanisms differ between peripheral nervous system (PNS) and central nervous system (CNS), we will discuss them consecutively. We will restrict ourselves to vertebrate SoxE proteins and if not stated otherwise refer to mouse proteins which are thought to function as their orthologs in other mammals. Rather than simply discussing functions, we will place our

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Fig. 1. SoxE proteins in NC development. (A) Conserved domains in SoxE proteins comprise dimerization domain (Dim), HMG domain, K2 domain and transactivation domain (TA). Numbers correspond to amino acid positions in mouse Sox10. (B) Sox8, Sox9 and Sox10 (red, green and blue bars) are expressed differentially in NC from specification to generation of neurons and glia. EMT, epithelial-to-mesenchymal transition. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.).

emphasis on the molecular mechanisms of SoxE proteins in their respective regulatory networks.

2. SoxE proteins and PNS SoxE proteins are neural crest (NC) specifiers downstream of and induced by neural plate border specifiers in vertebrates. In cooperation with other NC specifiers such as FoxD3, Twist, Snail and Id proteins and depending on phosphorylation and sumoylation events, they convey upon cells in the neural plate border region NC cell identity, ensure survival and confer the ability to undergo epithelial-to-mesenchymal transition [5–7] (Fig. 1B). In mammals, Sox9 precedes Sox8 and Sox10, and there is evidence that Sox9 induces expression of the others [5,8]. However, an absolute requirement for this order may not exist as analysis of NC induction in Xenopus leavis identified Sox8 as earliest and most important SoxE protein [9]. Furthermore, all three SoxE factors induce NC equivalently in experimental setups [7]. Most PNS neurons and almost all PNS glia are NC-derived. Before cells commit to a glial or neuronal fate, Sox9 and Sox8 are usually downregulated. Persistent Sox9 expression is only observed in subpopulations of cranial and cardiac NC cells and usually goes along with reciprocal extinction of Sox10 expression and an ectomesenchymal fate choice [10]. In trunk and vagal NC cells, downregulation of Sox9 and Sox8 occurs around delamination [8] (Fig. 1B). It follows that PNS defects observed after loss or mutation of Sox9 or Sox8 can only be a consequence of misregulations in early NC development. Such defects have not been observed for Sox8 in mammals [11]. However, they are detectable in mice with Sox9 deletion and in patients with heterozygous SOX9 mutations, although the most prominent symptoms in these Campomelic Dysplasia patients constitute skeletal malformations and XY sex reversal because of essential Sox9 functions during chondrocyte and Sertoli cell development. Sox9 compensates Sox8 loss, whereas Sox8 cannot fully rescue loss of Sox9. This non-reciprocal functional compensation among SoxE proteins is observed in several instances during development. When involved, Sox8 is usually the SoxE protein with the lower compensating capacity in mammals (see below).

Considering that Sox10 is the SoxE protein with continued expression in non-ectomesenchymal NC cells after delamination (Fig. 1B), its function as a major regulator of NC and PNS development is not surprising. Sox10-deficient mice and patients with heterozygous SOX10 mutations exhibit multiple NC defects affecting melanocyte lineage, enteric nervous system, and other parts of the PNS [12–15]. Resulting neurocristopathies in humans are referred to as Waardenburg syndrome, Hirschsprung disease and PWH, representing a combination of Waardenburg syndrome and Hirschsprung disease with peripheral neuropathy. Phenotypic heterogeneity of SOX10 mutations is believed to be caused by differences in genetic background and different mode of action of mutant proteins [16–19]. Similar to other essential regulators of development, Sox10 expression is controlled by a super-enhancer [20–22]. Depending on whether NC cells develop into glial cells (i.e. Schwann cells along nerves, satellite glia in ganglia or enteric glia in the gut) or neurons (sensory or autonomic), Sox10 expression differs (Fig. 1B). In neurons, Sox10 is turned off before maturation, whereas glial cells continue to express Sox10 [23,24]. In constitutively Sox10-deficient mice, PNS glia are not specified [12,25] (Fig. 2A). An active role of Sox10 in glial fate specification was confirmed in NC cultures [26]. During this process Sox10 is controlled in its expression by histone deacetylase (Hdac) 1 and 2, and cooperates with these chromatin modifying enzymes and the Pax3 transcription factor [27] (Fig. 2A,B). Direct target genes in early specified glia are ErbB3 and Desert Hedgehog (Dhh) [12,28,29]. ErbB3 forms a heterodimer with ErbB2 and acts as receptor for neuregulins as essential factors for glial survival and development. Sox10 remains functional after glial specification. As embryogenesis proceeds, the early Schwann cell (SC) precursor that depends on neuregulins as survival factors, first develops into an immature SC that relies on autocrine survival factors and is in contact with axon bundles [30]. SC-dependent axonal sorting leads to a promyelinating SC in a one to one relationship with an axonal segment as a prelude to terminal differentiation and myelin sheath formation by the myelinating SC (Fig. 2A). Using mouse mutants where Sox10 was conditionally deleted at specific SC stages or replaced by mutant versions, a continued requirement of Sox10 in SCs was shown [3,31–33]. The transitions from the immature to

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Fig. 2. SoxE proteins in SC development. (A) Sox10 (blue bar) is expressed at all stages including SC precursor (SCP), immature SC (iSC), promyelinating SC (pro-mSC) and myelinating SC (mSC). It interacts with different transcription factors (Pax3, Nfat, Oct6, Krox20) to activate target genes (ErbB3, Dhh, Oct6, Krox20, myelin genes, miR338) and perform the listed stage-specific functions. (B) Chromatin and transcription-related complexes are additionally recruited. Note that Figs. 2–4 show functional interactions which may or may not involve physical interactions on or off DNA, with SoxE monomers or dimers.

the promyelinating SC and from the promyelinating to the myelinating stage depend as much on Sox10 as myelin maintenance and SC homeostasis in the adult PNS (Fig. 2A). Several studies have clarified how Sox10 functions on a molecular level in SCs. Sox10 cooperates with chromatin modifying enzymes such as Hdac1 and Hdac2, and with chromatinremodelling machinery such as the Brg1-containing BAF-complex by recruiting them physically to essential target genes (Fig. 2B) [34,35]. This argues that Sox10 helps to convert chromatin into an open state and functions as a pioneer factor. As expected for a transcription factor that frequently acts on enhancers [36], Sox10 also cooperates and interacts with the Mediator complex [37]. This involves direct binding to the Med12 subunit. Sox10 induces stage-restricted transcriptional regulators of SC development that are then recruited as cooperation partners to activate specific sets of target genes. This may include further transcriptional regulators for progression to the next stage. These positive feed-forward loops represent an essential mechanism by which Sox10 drives lineage progression. To illustrate the principle: In immature SCs, Sox10 induces Oct6 [3,38] (Fig. 2A). Sox10 and Oct6 then cooperatively activate the program required for progression into the promyelinating stage. Among the joint targets is Krox20/Egr2 [39,40]. Induction of this zinc finger transcription factor further requires the action of Nfat proteins as additional Sox10 interactors [41]. Krox20/Egr2 then teams up with Sox10 to globally activate the terminal differentiation and myelination program [42]. This may not only occur at the level of transcription initiation, but may include stimulatory effects on transcriptional elongation as Sox10 physically and functionally interacts with the positive transcriptional elongator P-TEFb [43] (Fig. 2B). There are many microRNAs among Sox10 targets that exhibit stage-specific variations in expression levels and have been implicated in the regulation of glial development [44]. They may be instrumental for establishment of Sox10-dependent negative feedback loops and extinction of earlier Sox10-initiated programs as glial development proceeds. Although SoxE proteins can function

as sumoylation-dependent and Groucho-recruiting transcriptional repressors [45], they mainly act as activators and may heavily rely for repressive actions on indirect mechanisms and microRNAs. In contrast to peripheral glia, sensory PNS neurons do not absolutely require Sox10 as some neurons are specified in dorsal root ganglia of Sox10-deficient mice [12]. Nevertheless, Sox10 contributes to specification by regulating Neurogenin1 as shown in zebrafish [46]. Later on, Sox10 expression is extinguished in neuronal precursors (Fig. 1B). This is needed as Sox10 suppresses neuronal differentiation [47] and probably involves several mechanisms including regulated export from the nucleus using the functional nuclear export signal in Sox10 [48]. Such subcellular redistribution has been observed in SCs infected by leprosy bacteria where it is believed to cause loss of SC identity and initiate transformation to stem-like cells [49]. Additionally, Sox10 contains a phosphorylation-sensitive degradation signal [50]. Gsk3betadependent phosphorylation of this phosphodegron downstream of Wnt signalling and consecutive polyubiquitination may also contribute to rapid removal of existing Sox10. Once Sox10 protein levels decrease, Sox10 expression is also affected as the gene is subject to autoregulation [4]. Long lasting repression of Sox10 in sensory neurons probably involves further epigenetic mechanisms, such as methylation of its promoter. Sox10 promoter methylation has been shown to put an end to NC cell generation during chicken development and in that context depends on Dnmt3b [51].

3. SoxE proteins and CNS While present at the very onset of PNS development, SoxE proteins are missing in the early CNS. Neither neural plate nor early neural tube cells express SoxE proteins—with the exception of those that become NC (see above). Instead SoxB factors Sox2 and Sox3 prevail [52]. They may be involved in SoxE gene induction and remain expressed with SoxC, SoxD and SoxE proteins during further CNS development.

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At early stages, neuroepithelial cells self-renew or give rise to neurons, but not glia. In that sense they do not yet possess the full multipotentiality that is a defining feature of neural stem cells. The onset of SoxE expression coincides with the appearance of true neural stem cells [53]. In most CNS areas, Sox9 is present before Sox8 which in turn precedes Sox10 [54–56]. Only Sox9 and Sox8 are broadly expressed in neuroepithelial precursor cells throughout the ventricular zone. Sox9 is the primarily responsible SoxE factor for induction and maintenance of neural stem cells [53]. It is also essential for glial specification which is dramatically reduced after conditional Sox9deletion in the mouse spinal cord as a simple model for the CNS [54] (Fig. 3A,B). This affects generation of oligodendrocyte precursors (OPCs) from the pMN domain, but also generation of astrocyte precursors from other ventricular zone regions (Fig. 3A,B). Supernumerary motor- and interneurons are transiently generated at the expense of glial cells arguing that Sox9 is an important component of the mid-embryonic gliogenic switch. Deletion of the co-expressed Sox8 had no effect by itself, but exacerbated the gliogenic defect caused by loss of Sox9 pointing to non-reciprocal functional redundancy [56]. After glial specification Sox9 expression continues in astrocyte and oligodendrocyte lineages. However, levels are high in astrocyte precursors and much lower in OPCs [54], pointing to differential relevance of Sox9 in the two types of CNS glia. In astrocyte precursors Sox9 is downstream of Notch signalling, induces NFIA during specification and then cooperates with this transcription factor to activate a battery of astrocytic genes (among them Apcdd1, Mmd2 and Nfe2l1) with key roles in migration, metabolism and transcriptional regulation [57–59] (Fig. 3A). Sox9 and its target NFIA are also expressed during and required for oligodendroglial specification which in the early mouse spinal cord occurs in the pMN domain of the ventricular zone (Fig. 3B). During specification, Sox10 is rapidly induced in OPCs as they emigrate from the pMN domain. Induction requires Sox9 and the bHLH transcription factor Olig2 [60] whose expression is restricted at this time to the pMN domain. From then on, both Olig2 and Sox10 continue to be expressed in oligodendroglial cells as lineage markers. Concomitant with Sox10 appearance, Sox9 expression is reduced [54]. Sox8 continues to be expressed at steady levels in OPCs [56]. One of the consequences of Sox10 induction is that NFIA now engages preferentially in interactions with this SoxE protein (Fig. 3B). However, this interaction is not cooperative as with Sox9 in astrocytes but antagonistic. It functionally restricts NFIA in OPCs and suppresses astrocyte differentiation [61]. Despite many indications of functional redundancy, SoxE factors thus seem capable of exerting opposite effects in select properties and situations. The differential behaviour of Sox9 and Sox10 towards NFIA is an essential determining factor in glial sub-lineage diversification and is recapitulated under pathological conditions in the generation of glioma subtypes [61]. In OPCs SoxE proteins are responsible for Pdgfra expression and as a result for survival, proliferation and proper migration [62] (Fig. 4A). Sox10 and Sox9 are functionally redundant as dramatic Pdgfra reduction requires deletion of both Sox9 and Sox10. At the time of birth, the first OPCs in the spinal cord initiate terminal differentiation and start the myelination program. This includes induction of myelin gene expression, increased lipid biosynthesis and myelin sheath formation. The dramatic changes in overall gene expression go along with loss of Sox9 and substantially increased Sox10 expression [54,63]. Sox8 continues to be expressed at levels comparable to those in precursors [55] (Fig. 4A). Analyses of mouse models reveal an essential role of Sox10 in terminal differentiation of oligodendrocytes and myelination. Mice with conditional oligodendroglial Sox10 deletion suffer from severe dysmyelination [64], a defect that is also observed in combination

with PWH in some patients with heterozygous SOX10 mutations and then referred to as PCWH [17,65]. In mice, very few myelin sheaths and little myelin gene expression are detectable. Analysis of compound mutants confirmed that residual myelin gene expression is attributable to Sox8 activity [56,64]. As already described before, there is some redundancy between SoxE proteins, but compensation by Sox8 is far from complete. Mice that express Sox8 instead of Sox10 still exhibit a severe oligodendroglial differentiation defect [66]. The structural basis for this difference between Sox10 and Sox8 is not known. During terminal differentiation of oligodendrocytes Sox10 directly targets many genes that contribute to myelination. This has been analysed on single gene level for many of the relevant regulatory regions [63,64,67,68], but was also confirmed on a global scale [36] (Fig. 4A). In this respect, Sox10 acts similarly in CNS and PNS. However, even when activating the same target gene, Sox10 frequently uses different regulatory regions in SCs and oligodendrocytes. Furthermore, Sox10 cannot rely for activation of terminal differentiation genes in oligodendrocytes on its main cooperation partner in SCs, as Krox20/Egr2 is not expressed during oligodendrocyte development. Thus, it has to use different partners. One is the bHLH factor Olig1 that like Sox10 is predominantly active during oligodendroglial differentiation and activates myelin gene expression synergistically with Sox10 [69]. Another partner is the Ntd80-domain containing transcription factor Myrf (also known as Mrf or Gm98) [70] (Fig. 4A). Intriguingly, Myrf is under direct transcriptional control of Sox10, and is induced in oligodendroglial cells shortly before the onset of terminal differentiation. Produced as a transmembranous ER protein, it cleaves autoproteolytically, enters the nucleus and activates many terminal differentiation genes in combination with Sox10 as evident from co-occupancy and synergistic activation of regulatory regions [64,71]. Despite its completely different structure, Myrf in oligodendrocytes is thus functionally equivalent to Krox20/Egr2 in SCs. Another transcription factor that cooperates with Sox10 on oligodendroglial differentiation genes is Tcf7l2/Tcf4 [72] (Fig. 4A). It has been proposed that Tcf7l2/Tcf4 switches interaction partners downstream of Wnt signalling so that it performs different functions in cooperation with Kaiso in OPCs and with Sox10 in differentiating oligodendrocytes. The functional link between Sox10 and the Mediator complex reported in SCs has also been observed in differentiating oligodendrocytes [37] (Fig. 4B). Sox10 co-localizes on many regulatory regions in differentiating oligodendrocytes with chromodomain helicase DNA-binding protein 7 (Chd7) which is a target of Olig2 and Brg1, and serves as ATP-hydrolyzing subunit of chromatin remodelling complexes [73] (Fig. 4B). The intimate link between Sox10 and the Chd7 chromatin remodeller in differentiating oligodendrocytes is reminiscent of the functional connection between Sox10 and the Brg1-containing BAF complex in SCs (see above). Again, mechanistic principles of Sox10 action appear comparable between both types of myelinating glia, while exact cooperating partners differ. The choice of different partners is further supported by the lack of a clear functional link between Sox10 and Brg1 in differentiating oligodendrocytes [74]. Rather than acting as an interaction partner for Sox10, Brg1containing BAF complexes are essential for Olig2-dependent Sox10 induction during OPC specification, and at least part of the BAF effects on oligodendrocyte differentiation seem to be secondary to that [74,75]. Activation of the homeodomain protein Nkx2.2 and maintenance of Olig2 expression also require Sox10 [76,77]. Nkx2.2 is induced in the mouse oligodendrocyte lineage shortly before terminal differentiation as a transcriptional repressor. One of the genes it represses is Pdgfra and this repression is a decisive event for OPCs to develop into myelinating oligodendrocytes [78]. By inducing Nkx2.2, Sox10 helps to end expression of Pdgfra. Sox10 is thus

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Fig. 3. SoxE proteins and lineage decisions in CNS glia. (A) Neuroepithelial cells in the ventricular zone (VZ) express Sox9 and its target NFIA. In most regions, they jointly induce Apcdd, Mmd1, Nfe211 and other targets to generate astrocytes. (B) In the pMN domain of the VZ, additional Olig2 expression leads to Sox10 induction and OPC generation. Once present, Sox10 inactivates NFIA and induces alternate targets such as Pdgfra with its cooperation partners Sox5 and Sox6 (Sox5/6).

not only responsible for Pdgfra expression in OPCs, but also for its termination prior to oligodendrocyte differentiation. There are further ways by which Sox10 influences Pdgfra expression. Sox10 induces Sox6 in OPCs [79] (Fig. 4A). Sox6 and the closely related Sox5 cooperate with Sox10 on the Pdgfra promoter and jointly activate Pdgfra expression in a circuit that is reminiscent of the positive feed-forward loops observed during SC development [80] (Fig. 3B). At the same time, Sox5 and Sox6 prevent Sox10 from activating terminal differentiation genes in OPCs [79]. The same also holds for the bHLH transcription factor Hes5 that directly represses myelin gene expression but also interferes indirectly with their activation by sequestration of Sox10 [81] (Fig. 4A). Therefore terminal differentiation of OPCs requires extinction of Sox5, Sox6 and Hes5 expression as it allows Sox10 to switch to alternative partners such as Myrf and Olig1. Intriguingly, Sox6, Hes5 and Pdgfra transcripts are all targeted by microRNAs that are upregulated in the oligodendroglial lineage shortly before the onset of terminal differentiation such as miR219, miR138 and miR338 [82,83]. Considering that at least miR338 is under direct control of Sox10 [44], microRNA-containing negative feedback loops may help Sox10 to extinguish expression of its OPC partner proteins and change the oligodendroglial regulatory network in preparation for terminal differentiation. It is intriguing that a transcription factor has different regulatory functions in OPCs and oligodendrocytes, and that the same protein is additionally

involved in inducing the ordered transition from precursors into differentiating cells. 4. Conclusions While functions of SoxE proteins in PNS and CNS have been largely determined in the 1990s and early 2000s, the last ten years have provided substantial insights into the molecular mechanisms that underlie these functions. SoxE proteins interact with and exploit the help of a large number of transcription factors that vary with cell type and developmental stage [84]. They furthermore influence chromatin structure by recruiting chromatin modifying and remodelling machinery. Even their impact on the transcription process itself is manifold. It involves interactions with various accessory components of the transcription machinery such as the Mediator complex or P-TEFb, and may affect elongation as well as initiation. Intriguingly, SoxE proteins influence expression of interaction partners either directly or via microRNAs. As consequence of transcription factor interactions and microRNA inductions regulatory circuits are established that allow SoxE proteins to maintain cells in a defined developmental stage, but also to evoke transition from one state to the next during lineage progression. Despite this detailed knowledge there are still unresolved issues. It is puzzling why SoxE proteins often function redundantly, but sometimes elicit antagonistic functions as exemplified by the proastrocytic action of Sox9 and the anti-astrocytic action of Sox10

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Fig. 4. SoxE proteins in oligodendroglial development. (A) SoxE proteins (red, green and blue bars) are differentially expressed in OPC, pre-myelinating oligodendrocyte (pre-mOL) and myelinating oligodendrocyte (mOL). They interact with different transcription factors (Sox5, Sox6, Hes5, Tcf7l2, Olig1, Myrf), and activate target genes (Sox6, Pdgfra, Nkx2.2, Myrf, myelin genes, miR338) to perform the listed stage-specific functions. (B) Chromatin and transcription-related complexes are additionally recruited. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

during CNS development. Similarly, the role of Sox8 is still illdefined. As it stands, Sox8 is co-expressed with Sox9, Sox10 or both in neuroepithelial or glial precursors, but hardly ever plays a decisive role. The question arises whether Sox8 just contributes a minor non-essential fraction to the overall SoxE function or whether it has some unique roles. A function in select populations of CNS neurons seems possible [11]. Regulatory regions often bind SoxE proteins as dimers via inverted repeats of the Sox consensus [85–87] and frequently contain additional, functionally relevant monomeric sites [4,40,64,77]. It is currently unclear to what extent and how SoxE dimers and monomers contribute to overall function and whether interactions with other transcription factors specifically require one or the other. In vitro, SoxE proteins form homodimers and heterodimers with each other [85–87]. If heterodimers exist in vivo, they may represent a further means of modulating SoxE function in coexpressing cells. Finally, it is obvious that SoxE activity must be tightly controlled by signals. The existence of such signal input is evident from the many posttranslational modifications found on SoxE proteins including phosphorylations, acetylations and sumoylations. However, there is little knowledge about the nature of the signals and their convergence on the various SoxE factors. Signals may influence the properties of SoxE factors and the choice of interaction partners, but also affect protein stability. The resulting changes in protein amounts may be highly relevant as SoxE functions in mice and men appear very sensitive to that [14,77]. All this warrants and will be the subject of further investigations.

Acknowledgements We apologize to all whose contributions were not cited due to space limitations. The authors’ work is supported by grants from the DFG (We1326/8, We1326/11 and We1326/12), the Bavarian State Ministry of Education and Culture, Science and Arts in the framework of the Bavarian Research Network Induced Pluripotent Stem Cells (ForIPS), and the IZKF (TP E18 and D24).

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