Sox box protein 15: Biological Overview | References
Gene name - Sox box protein 15
Synonyms - Sox50E, SoxF
Cytological map position - 50E4-50E4
Function - transcription factor
Symbol - Sox15
FlyBase ID: FBgn0005613
Genetic map position - 2R:10,088,888..10,099,914 [-]
Classification - SOX-TCF_HMG-box, class I member of the HMG-box superfamily
Cellular location - nuclear
Wnt molecules act as mitogenic signals during the development of multiple organs, and the aberrant activity of their pathway is often associated with cancer. Therefore, the production of Wnts and the activity of their signaling pathway must be tightly regulated. This study has investigated the mechanisms of this regulation in the Drosophila hinge, a domain within the wing imaginal disc that depends on the fly Wnt1 ortholog wingless (wg) for its proliferation. The results uncover a new feedback loop in the wg pathway in which the spatially restricted activation of the Sox gene SoxF (Sox15) by wg represses its own transcription, thus ensuring tight regulation of growth control. rotund, a wing proximodistal patterning gene, excludes SoxF from a thin rim of cells. These cells are thus allowed to express wg and act as the source of mitogenic signal. This novel mode of action of a Sox gene on the Wnt pathway -- through transcriptional repression of a Wnt gene -- might be relevant to human disease, as loss of human SoxF genes has been implicated in colon carcinoma (Dichtel-Danjoy, 2009).
One of the long-standing questions in biology is how organ growth is coordinated with tissue patterning. Research during recent decades has shown that a limited set of signals and signaling pathways control this coordination. Some of these signals are mitogenic, and their production at specific sites, called signaling centers, links spatial information to cell proliferation within developing organs. Normal organ growth not only needs mitogens, but also mechanisms to control their production, transport, reception and/or transduction to ensure that proliferation is limited in space and time. Alterations in these control mechanisms often lead to disease (Dichtel-Danjoy, 2009).
The Wnt/β-catenin signaling pathway promotes cell proliferation during normal development and disease. Wnts are lipid-modified glycosylated signaling molecules that can reach distant cells. Binding of Wnts to the receptor complex [composed of a Frizzled family receptor and an Arrow (LRP) co-receptor] results in the stabilization of the transcriptional co-factor β-catenin [armadillo (arm) in Drosophila]. Thereby, β-catenin/Arm accumulates in the nucleus, where it associates with Tcf/LEF DNA-binding transcription factors to regulate the expression of Wnt target genes. Research in a number of model organisms has demonstrated that the Wnt/β-catenin pathway controls cell proliferation in a variety of tissues, including the nervous system and the progenitors of the intestine and hematopoietic systems in mammals, and during imaginal disc development in Drosophila. It is also known that most colorectal tumors, and a number of other tumor types, are caused by aberrant Wnt/β-catenin signaling, which underlines the necessity of tight regulation of this pathway (Dichtel-Danjoy, 2009).
The range and intensity of the signaling elicited by Wnt molecules have been shown to be regulated by many different mechanisms, including negative-feedback loops. These have been particularly well studied for the main Drosophila Wnt gene, wingless (wg). wg is required in the imaginal discs for the growth and patterning of the adult body structures. wg signaling results in the downregulation of its two receptors, Dfz-2 (fz2 - FlyBase) and fz and in the upregulation of Dfz-3 (fz3 - FlyBase), a non-productive low-affinity receptor, and of the extracellular Wg inhibitor Notum (wingful). Intracellularly, high levels of wg/Wnt signaling induce the expression of two inhibitors of the pathway: naked cuticle and nemo. All these feedback loops result in an attenuation of the signal at the sites of maximal wg production and are generally implicated in all processes in which wg is required (Dichtel-Danjoy, 2009).
The Drosophila wing disc gives rise to the wing blade, the notum (body wall) and the hinge, which joins the wing blade to the body wall and articulates its movements. wg is expressed in two concentric rings in the hinge domain and has been shown to be required for the proliferation of hinge cells. Moreover, wg overexpression is sufficient to drive hinge overgrowths without causing major repatterning. Therefore, the precise regulation of the wg pathway is crucial to control the growth of the hinge. The mitogenic effect of wg on hinge cells contrasts with its effect on the neighboring wing pouch cells which, upon similar wg overexpression, are mostly driven into sensory organ differentiation. One prediction from these results is that the hinge-specific proliferative function of wg needs dedicated control mechanisms to ensure normal hinge size and shape. To identify these mechanisms, genes were sought that are differentially expressed in the hinge territory for a role in wg-mediated proliferation. SoxF (Sox15) belongs to the family of sequence-specific HMG Sox transcription factors and has been shown to be expressed in the prospective hinge of third larval stage (L3) wing discs (Cremazy, 2001). The functions of Sox genes have been extensively studied in mammals, in which they play essential roles during development. In addition, misregulation of Sox genes is often associated with cancer (Dichtel-Danjoy, 2009).
Only two of the eight Sox family genes present in the Drosophila genome have been studied in detail: Dichaete (D) and SoxNeuro (SoxN). They belong to the SoxB group and have prominent roles in embryonic segmentation and nervous system development. In addition, it has recently been shown that both genes negatively regulate the activity of the wg/Wnt pathway during cell fate specification in the embryonic epidermis (Chao, 2007; Overton, 2007; Dichtel-Danjoy, 2009 and references therein).
This paper reports that SoxF, which is the sole member of this Sox group in Drosophila, is also required to restrain wg signaling, but using a novel mechanism: the transcriptional repression of wg. In the absence of SoxF, wg transcription spreads through the hinge causing its overproliferation. SoxF is itself under the control of the canonical wg/Wnt pathway such that wg and SoxF regulate each other's transcription through a feedback loop. Moreover, the expression of rotund (rn), which is part of the proximodistal patterning mechanism of the wing disc, allows the exclusion of SoxF from a thin rim of cells, allowing them to express wg. Thereby, this rim becomes a spatially well-defined mitogen-producing center necessary to ensure normal hinge growth. This novel mode of action of a Sox gene on the Wnt pathway -- the transcriptional repression of a Wnt gene -- might be relevant to human disease, as loss of human SoxF genes has been implicated in colon carcinoma (Dichtel-Danjoy, 2009).
In order to determine the role played by SoxF during hinge development, a SoxF allele, Sox15KG09145 (now renamed SoxFKG09145) was characterized. The SoxFKG09145 allele carries an insertion of the P[SUPor-P] transposon in an intronic region of the gene, which also harbors the CG30071 transcript. Most homozygous SoxFKG09145 flies die as pharate adults, and escapers are weak with held-out wings. This latter phenotype is indicative of hinge defects. In fact, these flies show abnormal proximal hinge structures: the sclerites, the alula and the costa are affected. Although the insertion does not affect SoxF coding sequence, it was observed by RT-PCR and in situ hybridization that SoxF expression is completely lost in the wing disc of mutant L3 larvae. Sice this P-element carries insulator sequences, it was also checked by RT-PCR that expression of CG30071 and of the 5' neighboring gene, RpS23, was not affected by the insertion, which was indeed the case. This study has also generated new alleles by imprecise excision of the P transposon from the original allele. In addition to full revertants, more than ten mutant lines were isolated in which different lengths of intron sequences were deleted, without affecting the coding region, and which showed a range of phenotypic severity. These results suggest that this intronic region carries crucial elements for the regulation of SoxF expression. Some alleles were isolated that disrupt the coding sequence. Among them, SoxF26 is specific to the SoxF gene and deletes the first exon and part of the first large intron, and is therefore likely to be a null allele. This allele has the same phenotype as the initial insertion. In addition, the phenotype and escaper rates of individuals carrying SoxFKG09145 over a deficiency uncovering the SoxF locus, Df(2R)Exel7130, are the same as for homozygous SoxFKG09145 flies. Therefore, SoxFKG09145 behaves as a genetic null allele. Cremazy (2001) reported that SoxF is expressed in the embryonic Peripheral nervous system (PNS). Adult escapers of the molecular null allele SoxF26 exhibit, in addition to their abnormally folded wings, are also weak and die shortly after eclosion. Other hinge mutants, such as wg spd-fg, are much healthier. Therefore, it is possible that the larval lethality and weakness of adult escapers is due to abnormal PNS development (Dichtel-Danjoy, 2009).
This study describes a novel negative-feedback mechanism in the wg pathway that is required to restrain the expression of wg itself, and which is essential to control organ growth. During Drosophila development, the wg pathway often leads to the activation of genes that attenuate its signaling pathway. This is the case, for example, for Notum and Dfz-3, which are expressed in the wing disc in response to peak levels of signaling to reduce ligand availability for the Wg receptors, and for nemo, which acts intracellularly to block the signal transduction pathway. In all cases described, these negative-feedback components act in all domains of wg expression and none regulates wg expression at the transcriptional level. However, in the case investigated in this study, the putative transcription factor SoxF is activated non-autonomously by wg in a hinge-specific manner. SoxF in turn represses wg transcription driven by the wg spd-fg enhancer, thus restricting the production of wg to the thin inner ring (IR) domain. Interestingly, the SoxF phenotype is similar to those of dominant Dichaete (D) mutations. D is a SoxB gene not normally expressed in the wing disc. However, flies carrying dominant D mutations show reduced hinge structures. This phenotype is caused by ectopic D expression in the prospective hinge region of the disc. One of the salient features of D discs is the repression of the wg IR, which is reminiscent of the wg repression by SoxF described in this study. Therefore, and taking into account the similarity between Sox proteins in their HMG DNA-binding domain, the ectopic D might be mimicking the repression of wg that is normally exerted by SoxF (Dichtel-Danjoy, 2009).
The tight regulation of the growth of the hinge depends critically on the wg-induced activation of SoxF in the growing territory. Nevertheless, this activation is 'polarized' along the PD axis, taking place only in cells adjacent and proximal to the IR. It is proposed that this directionality in SoxF activation results from the mechanisms that pattern the wing disc along its PD axis. It has been suggested that wg is activated non-autonomously by a signal produced by the vg-expressing wing pouch cells, but excluded from them (del Alamo Rodriguez, 2002). This would generate a circular domain of wg expression surrounding the wing pouch. However, in the absence of SoxF, the domain of wg is abnormally broad and causes hinge overgrowth. This ectopic wg expression does not seem to result from a misregulation of hinge-specific genes: the expression of nub, tsh, hth and rn and their relative positioning in the hinge are unaffected in SoxF mutant discs. Therefore, it seems that in the absence of SoxF, hinge cells cannot respond to the wg activating signals with enough precision to give rise to a thin ring of wg expression. The results show that this precision is achieved through a double repression mechanism. First, wg activates its own transcriptional repressor, SoxF. This would lead to the extinction of wg expression if it were not for rn, which acts as a repressor of SoxF. Second, rn, by repressing SoxF, permits wg transcription. The result is that wg expression becomes restricted to a narrow circular stripe at the edge of the rn domain that provides a highly localized source of Wg. This signal activates, simultaneously and in the same cells, proliferation and the upregulation of SoxF, which restricts the production of the signal. Therefore, SoxF joins SoxN and SoxD (Sox102F - FlyBase) (Chao, 2007; Overton, 2007) as the third Drosophila Sox known to antagonize the wg pathway. The vertebrate Sox proteins Sox9 (Mori-Akiyama, 2007), XSox3 (Zorn, 1999) and XSox17 (Sinner, 2004) have also been shown to downregulate the Wnt/β-catenin pathway. Therefore, this antagonism seems evolutionarily conserved (Dichtel-Danjoy, 2009).
The relationship between SoxF genes, the wg/Wnt pathway and the control of tissue proliferation seems to extend to disease. The SoxF Sox17 is normally expressed in the gut epithelium where it downregulates Wnt signaling via degradation of β-catenin and TCF. In colon carcinomas, the expression of the SoxB gene Sox17 is often reduced, and this is associated with tissue overproliferation (Sinner, 2007). Moreover, inactivation of the SoxE gene Sox9 leads to increased cell proliferation and hyperplasia in the mouse intestine (Bastide, 2007). The authors concluded that Sox9 is essential for the fine-tuning of the transcriptional activity of the Wnt pathway (Bastide, 2007). Interestingly, the expression of Sox9 is regulated by the Wnt pathway itself (Blache, 2004). These results in Drosophila point to the possibility that the transcriptional regulation of Wnt expression by Sox genes might be a common feature of this proliferation-associated feedback loop (Dichtel-Danjoy, 2009).
This study has investigated the expression and function of the Sox15 transcription factor during the development of the external mechanosensory organs of Drosophila. Sox15 is expressed specifically in the socket cell, and the transcriptional cis-regulatory module has been identified that controls this activity. Suppressor of Hairless [Su(H)] and the POU-domain factor Ventral veins lacking (Vvl) bind conserved sites in this enhancer and provide critical regulatory input. In particular, Vvl contributes to the activation of the enhancer following relief of Su(H)-mediated default repression by the Notch signaling event that specifies the socket cell fate. Loss of Sox15">Sox15
After Su(H), Sox15 is the second transcription factor gene known to be activated specifically in the postmitotic socket cell of the Drosophila external sensory organ lineage. Three observations reported here indicate that although both genes come to be expressed at high levels in this cell, the underlying regulatory logic may be quite different (Miller, 2009).
The first is the distinct dynamics of autoregulatory socket enhancer (ASE)-stimulated Su(H) transcription versus Sox15 expression. Su(H) is immediately activated at high levels following the specification of the socket cell, due at least in part to the establishment of an autoregulatory loop working through the Su(H) ASE. Sox15 expression, however, exhibits a significant delay between socket cell specification and the time peak levels of transcript accumulation are achieved (Miller, 2009).
The second observation concerns the role played by Vvl in the activation of the Sox15 socket enhancer and the Su(H) ASE (Barolo, 2000). Conserved within the ASE lies a motif, CATAAAT, that might act as a weak Vvl binding site, suggesting the possibility that Vvl could play a part in the high-level activation of Su(H) in the socket cell. However, this appears not to be the case, since ASE-GFP is activated within the same temporal window, and just as strongly, in vvl mutant clones as in neighboring wild-type tissue. By contrast, while the long reporter fragment Sox7.5 > GFP, covering the whole intron, is also activated in vvl mutant sensory organs, there is a substantial delay in this expression, which is often not detectable until the socket cell has begun to divide aberrantly. At this time, neighboring wild-type sensory organs are already strongly expressing Sox7.5 > GFP. Vvl thus appears to be one factor present in the socket cell that is necessary for the full activation of Sox15, but not of Su(H) (Miller, 2009).
Finally, there is the observed role of N-activated Su(H) in contributing to the transcriptional activation of the Sox15 socket enhancer versus the Su(H) ASE. A major difference between the two genes is made apparent by the contrasting effects on reporter gene expression of mutating the high-affinity Su(H) site(s) in their respective socket cell enhancers. In the case of the Su(H) ASE, mutation of the Su(H) sites causes a strong reduction in socket cell activity at early times, along with ectopic activity in the shaft cell; by the adult stage, the mutant enhancer is inactive. Thus, N-activated Su(H) contributes critically to the transcriptional activation of the Su(H) ASE. The Su(H)-site-mutant Sox15 enhancer, on the other hand, shows no apparent diminution of its socket cell activity early (when it also drives ectopic expression in the shaft cell), and remains fully active in the pharate adult. In the case of Sox15, then, activation of Su(H) by the N signaling event appears to serve only the purpose of relieving Su(H)-mediated default repression; activation of the enhancer is evidently accomplished entirely through the action of other factors such as Vvl. This distinction in the role of N signaling in enhancer activation has been referred to as 'Notch instructive' [Su(H) ASE] versus 'Notch permissive' (Sox15 socket enhancer) (Miller, 2009).
This investigation of the loss-of-function phenotype of Sox15 has revealed that, like Su(H), it has an important role in controlling the socket cell differentiation program. Comparison of the phenotypic effects of losing Sox15 function, Su(H) function, or both, suggests an incomplete overlap in the target gene batteries regulated by the two factors. Loss of either Sox15 or Su(H) ASE activity causes a serious defect in mechanosensory organ function. The lack of Su(H) ASE activity confers the more severe phenotype, including significant reductions of both transepithelial potential (TEP) and mechanoreceptor current (MRC). The TEP defect signifies an inability of the socket cell to establish the receptor lymph cavity itself, the proper ionic composition of the receptor lymph, or a combination of the two. The genes required for these events have yet to be identified, but it is likely that Su(H) plays a role in regulating their expression in the socket cell. Sox15, on the other hand, does not appear to share this role, based on the apparent lack of a major TEP defect in Sox15 mutants. Instead, Sox15 appears to regulate targets that contribute to socket cell viability. Without these target factors, the cell eventually becomes necrotic. In addition, the principal physiological phenotype of Sox15 mutants is the MRC defect, which is also conferred by loss of Su(H) ASE function. Loss of MRC is indicative of a failure in neuronal function, yet both Sox 15 and the Su(H) ASE are active specifically in the socket cell. This apparent paradox indicates an important role for the socket cell as a support cell for the mechanosensory neuron. To date three proteins - Sox15 (this paper), Su(H), and the cytochrome P450 Cyp303a1 - expressed in and required specifically for socket cell differentiation appear to contribute to neuronal function in mechanosensation. Given that the socket cell envelops the other cells of the sensory organ as it develops, the socket may be intimately involved in their normal differentiation and in the establishment of structural and functional connectivity between them. Defects in these processes could readily manifest themselves in an MRC phenotype. Thus, the abnormal microtubule bundling in the sensory dendrite in Sox15 mutants may very well be the result of a defect in the socket cell's ability to contribute as it should to the neuron's normal development. It is unclear at this point if the dendrite defect is due to a failure to activate Sox15-dependent target genes directly involved in the socket cell's support function, or if it is an indirect consequence of the degeneration of the socket cell (Miller, 2009).
Previous studies have established that both daughters of the pIIa secondary precursor division are bipotent cells that can adopt either the shaft or socket cell fate. Asymmetric N signaling specifies that the posterior daughter expresses only the signal-dependent socket fate and the anterior daughter only the signal-independent shaft fate. Correspondingly, investigation of socket cell fate specification has largely focused on its positive aspects; i.e., those ways in which the N signaling event promotes the socket cell from the 'default' (signal-independent) shaft fate to the alternative fate, triggering its execution of the distinctive socket differentiation program. This study has shown that socket cell-specific activation of Sox15 expression is an important component of this program. But the present study has also revealed the other side of the coin, by showing that the N signaling event also results in the activation of a mechanism for suppressing in the socket cell the capacity to execute the shaft differentiation program. This suppression mechanism involves the combined action of Sox15 and Su(H) in inhibiting transcription of the sv gene, which encodes a Pax transcription factor that is a high-level activator of the shaft differentiation program. Without this inhibition, the socket cell generates both socket and shaft cuticular structures. It is clear, then, that much of the network circuitry necessary for the execution of the shaft differentiation program remains intact in the socket cell even after its fate has been specified. These results show that robust N-mediated cell fate specification in the mechanosensory bristle lineage involves not only promoting the signal-dependent fate, but also actively inhibiting the alternative program (Miller, 2009).
It is likely that at least Su(H)'s role in inhibiting sv expression in the socket cell is indirect, and occurs via an as yet unidentified repressor. An attractive candidate for this factor X would be one or more basic helix-loop-helix (bHLH) repressors encoded in the Enhancer of split Complex [E(spl)-C]. Multiple E(spl)-C bHLH repressor genes are activated directly by Su(H) in response to N signaling in a variety of developmental contexts. Consistent with this possibility, it was observed that socket cell-specific overexpression of E(spl)m7-VP16, a form of the E(spl)m7 bHLH repressor that has been converted to a strong activator, phenocopies the ectopic-shaft effect of sv overexpression in the same cell (Miller, 2009).
The results of this and earlier studies afford a glimpse of the regulatory architecture of the socket differentiation program, which is set in motion by the N signaling event that specifies the socket cell fate. It seems useful to distinguish two broad phases of this program, which no doubt overlap each other in time and are also very likely to share at least some components of the regulatory network. These two phases might be referred to as the earlier 'morphogenetic' and the later 'physiological' subdivisions of the socket program. The distinction is prompted by the observations of the phenotypes conferred by loss of the two socket cell-specific transcription factor activities identified so far, Su(H) and Sox15. In both cases, it was found that many characteristic aspects of the socket's cellular differentiation proceed completely normally, most notably the construction of the complex socket cuticular structure that surrounds the shaft structure (morphogenesis). By contrast, loss of Su(H) or Sox15 function in the socket cell results in major deficits in the electrophysiological capacity of the sensory organ (physiological differentiation). As described above, the specifics of these deficits differ for Su(H) versus Sox15 mutants, and include distinctive cell-autonomous defects in the socket cell and defects in other cells likely due to the failure of some aspects of the socket cell's support function. But the phenotypic commonalities (emphasizing the physiological and not the morphogenetic) are striking nonetheless. It is perhaps reasonable to speculate that transcription factors like Su(H) and Sox15 that are activated for the first time in the sensory organ lineage specifically in the socket cell will tend to function primarily in the later physiological phase of the differentiative program. By contrast, it may be expected that the earlier morphogenetic phase is controlled primarily by factors first expressed earlier in the lineage, at least in the pIIa precursor cell and perhaps in the SOP. Vvl exemplifies this notion: It is first expressed in the SOP, and loss of its activity causes visible defects in the socket cuticular structure, as well as aberrations in the mitotic status of the normally postmitotic socket cell. Investigation of the roles of additional transcriptional regulators in directing the socket differentiation program will test the viability of this broad conceptual framework (Miller, 2009).
Overall, this comparison of the roles of Sox15, Su(H), and Vvl in controlling aspects of the socket differentiation program indicates that they function largely in parallel, and collaboratively, rather than in a hierarchical fashion. This may suggest that the socket program will prove to be characterized by an ensemble of such parallel regulatory inputs that collectively direct the complex differentiation of the cell. It is perhaps useful to note that this picture contrasts already with what is known about the control of the shaft differentiation program, which is dominated by the function of Sv as a high-level regulator. Whether this reflects some important difference in how the differentiative programs of N-responsive versus N-non-responsive cell types are controlled will become clearer as more is learnt about the gene regulatory network that underlies mechanosensory organ development (Miller, 2009).
Search PubMed for articles about Drosophila Sox15
Barolo, S., et al. (2000). A Notch-independent activity of Suppressor of Hairless is required for normal mechanoreceptor physiology. Cell 103: 957-969. PubMed ID: 11136980
Bastide, P., Darido, C., Pannequin, J., Kist, R., Robine, S., Marty-Double, C., Bibeau, F., Scherer, G., Joubert, D., Hollande, F. et al. (2007). Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J. Cell Biol. 178: 635-648. PubMed ID: 17698607
Blache, P., van de Wetering, M., Duluc, I., Domon, C., Berta, P., Freund, J. N., Clevers, H. and Jay, P. (2004). SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J. Cell Biol. 166: 37-47. PubMed ID: 15240568
Chao, A. T., Jones, W. M. and Bejsovec, A. (2007). The HMG-box transcription factor SoxNeuro acts with Tcf to control Wg/Wnt signaling activity. Development 134: 989-997. PubMed ID: 17267442
Cremazy, F., Berta, P. and Girard, F. (2001). Genome-wide analysis of Sox genes in Drosophila melanogaster. Mech. Dev. 109: 371-375. PubMed ID: 11731252
del Alamo Rodriguez, D., Terriente, J., Galindo, M. I., Couso, J. P. and Diaz-Benjumea, F. J. (2002). Different mechanisms initiate and maintain wingless expression in the Drosophila wing hinge. Development 129: 3995-4004. PubMed ID: 12163403
Dichtel-Danjoy, M. L., Caldeira, J. and Casares, F. (2009). SoxF is part of a novel negative-feedback loop in the wingless pathway that controls proliferation in the Drosophila wing disc. Development 136(5): 761-9. PubMed ID: 19176582
Miller, S. W., Avidor-Reiss, T., Polyanovsky, A. and Posakony, J. W. (2009). Complex interplay of three transcription factors in controlling the tormogen differentiation program of Drosophila mechanoreceptors. Dev. Biol. 329(2): 386-99. PubMed ID: 19232522
Mori-Akiyama, Y., van den Born, M., van Es, J. H., Hamilton, S. R., Adams, H. P., Zhang, J., Clevers, H. and de Crombrugghe, B. (2007). SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 133: 539-546. PubMed ID: 17681175
Overton, P. M., Chia, W. and Buescher, M. (2007). The Drosophila HMG-domain proteins SoxNeuro and Dichaete direct trichome formation via the activation of shavenbaby and the restriction of Wingless pathway activity. Development 134: 2807-2813. PubMed ID: 17611224
Sinner, D., Rankin, S., Lee, M. and Zorn, A. M. (2004). Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development 131: 3069-3080. PubMed ID: 15163629
Sinner, D., Kordich, J. J., Spence, J. R., Opoka, R., Rankin, S., Lin, S. C., Jonatan, D., Zorn, A. M. and Wells, J. M. (2007). Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol. Cell. Biol. 27: 7802-7815. PubMed ID: 17875931
Zorn, A. M., Barish, G. D., Williams, B. O., Lavender, P., Klymkowsky, M. W. and Varmus, H. E. (1999). Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Mol. Cell 4: 487-498. PubMed ID: 10549281
date revised: 20 February 2010
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