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Logo of ajpgiPublished ArticleArchivesSubscriptionsSubmissionsContact UsAJP - Gastrointestinal and Liver PhysiologyAmerican Physiological Society
Am J Physiol Gastrointest Liver Physiol. Apr 2011; 300(4): G503–G515.
Published online Feb 2, 2011. doi:  10.1152/ajpgi.00489.2010
PMCID: PMC3302185

Sry-box (Sox) transcription factors in gastrointestinal physiology and disease

Abstract

The genetic mechanisms underlying tissue maintenance of the gastrointestinal tract are critical for the proper function of the digestive system under normal physiological stress. The identification of transcription factors and related signal transduction pathways that regulate stem cell maintenance and lineage allocation is attractive from a clinical standpoint in that it may provide targets for novel cell- or drug-based therapies. Sox [sex-determining region Y (Sry) box-containing] factors are a family of transcription factors that are emerging as potent regulators of stem cell maintenance and cell fate decisions in multiple organ systems and might provide valuable insight toward the understanding of these processes in endodermally derived tissues of the gastrointestinal tract. In this review, we focus on the known genetic functions of Sox factors and their roles in epithelial tissues of the esophagus, stomach, intestine, colon, pancreas, and liver. Additionally, we discuss pathological conditions in the gastrointestinal tract that are associated with a dysregulation of Sox factors. Further study of Sox factors and their role in gastrointestinal physiology and pathophysiology may lead to advances that facilitate control of tissue maintenance and development of advanced clinical therapies.

Keywords: Sox, repair, proliferation, stem cells, cancer

contemporary biomolecular research promises to advance gastroenterology in the 21st century by providing clinicians and researchers with a growing understanding of the molecular mechanisms that underlie both normal physiology and disease of the gastrointestinal (GI) tract. As the basic and clinical research communities grow closer to bridging the gap between bench and bedside, it is apparent that an understanding of cellular maintenance and tissue repair mechanisms is central to achieving this goal. Sox [sex-determining region Y (Sry) box-containing] factors are a family of structurally related transcription factors that are emerging as regulators of transcriptional activity with potent effects on cellular phenotypes. This review will focus on the current understanding of the role of Sox factors in normal cellular maintenance and differentiation, as well as in disease states of the endodermally derived tissues of the GI tract.

The GI tract, which includes the esophagus, stomach, and small and large intestine, is constantly exposed to microbes, chemical toxins or mutagens, varying pH, and physical injury to the epithelial barrier. The consequences of compromising the epithelial barrier of the GI tract are leakage of bacteria into the surrounding vasculature, leading to sepsis; or leakage of acid into the underlying mesenchyme, resulting in ulcers and chronic inflammation. Therefore, tissue renewal driven by epithelial stem cells is critical to maintaining constant integrity of epithelial barriers and ultimately the survival of the organism.

In addition to maintaining basal function, tissue-specific stem cells are capable of responding to injury, damage, or even large-scale loss of tissue to attempt repair. For example, intestinal epithelial stem cells undergo expansion and drive massive tissue remodeling following ileo-cecal resection (23). However, stem cell populations do not always respond equally to damage. Following pancreatectomy, ductal cell populations of the rat pancreas are able to regenerate a large portion of the organ's original mass, but, in the case of type 1 diabetes, there are no regenerative processes that replace destroyed β-islet cells (9). Further complicating the understanding of stem cell-mediated regeneration is the observation that conventional animal models do not always exhibit responses that translate to human biology. For instance, recent findings indicate that β-islet cell regeneration does not occur following pancreatectomy in adult human patients, as previously observed in rats (9, 63). Aberrant proliferation of tissue-specific stem cells is implicated in a wide range of common diseases throughout the GI tract, including diabetes, cirrhosis, and GI cancers (59, 61, 80, 112). The differential abilities of stem cell pools to respond to regenerative stimuli point to intrinsic genetic components that influence the stemness of the cell and are capable of reacting to extrinsic cues.

Attempts to expand on the nascent understanding of stem cell maintenance and differentiation in the GI tract have led to the identification of several gene families implicated in the growth and expansion of multipotent stem cell populations. Among these families is a group of genes known as Sox transcription factors. Founding members of the Sox family were first described in terms of their role in establishing sexual dimorphism in development (34, 51, 81). Shortly thereafter, Sox factors were identified in adult neural cell populations, where they were shown to have powerful roles in maintaining tissue-specific stem cell populations within the nervous system (18, 81, 95).

A common theme in recent studies is that Sox factors possess a potent capacity to direct or influence “stemness,” or a cell's ability to meet the established stem cell criteria of multipotency and self-renewal. Landmark studies demonstrated that Sox2, along with two other transcription factors, possessed the ability to reprogram differentiated adult cells to a state of pluripotency, resembling that seen in embryonic stem cells (88, 89). Taken with the cell-specific expression patterns and redundant function of Sox factors, the demonstrated ability of Sox2 to regulate cellular potency suggests that Sox factors might play a role in maintaining stemness in cells of the GI tract.

SOX FACTORS: VERSATILE REGULATORS OF TRANSCRIPTIONAL ACTIVITY

There are currently 30 described Sox factors in mammals. The first Sox gene characterized was Sry. Sry was identified as the previously reported testis-determining factor in sex-reversed human XX males and XY females (81). Sox factors represent a family of genes within the high-mobility group (HMG) superfamily, demonstrating homology in their 79-amino acid HMG-box, DNA-binding domain motifs (34, 81, 84). All Sox factors exhibit a conserved HMG domain motif of RFMNAF, which distinguishes them from other HMG-box genes (7). However, it has been observed that all Sox factors, with the exception of Sry, have an extended motif homology of RFMNAFMVW, and it has been suggested that this homology sequence be used for classification of Sox factors (7). The HMG box has the capacity to bind both DNA consensus elements and other transcriptional regulators, such as POU-domain proteins, to modulate transcriptional activity (2, 110). All Sox factors studied to date demonstrate the ability to bind a DNA consensus sequence of (A/T)(A/T)CAA(A/T)G, allowing these factors to sometimes exhibit functionally redundant roles (18, 19, 24, 31, 37, 40, 96). Phylogenic analysis of Sox factor HMG-box sequence and protein structure has identified similarities between different Sox genes that have resulted in the classification of Sox factors into subgroups A-J (7).

Sox factors share a striking ability to affect structural changes in DNA. Sox factors have been shown to bind the minor groove of the DNA helix, resulting in a significant degree of DNA bending not elicited by other members of the HMG superfamily that bind to specific DNA sequences (27, 31). The participation of Sox factors in regulating a conformational change in DNA suggests that these factors may possess powerful transcriptional modulating roles that go beyond the function of site-specific transcriptional activation and implies an effect on larger order chromatin structure (27).

Observations regarding the architectural effect of Sox factors on DNA highlight the significance of this property. Early studies on the role of Sry in sex reversal revealed that most aberrant mutations occur in the HMG domain, suggesting that DNA binding and bending properties are essential in sex determination (27, 71). It has been proposed that, by affecting a dramatic conformational change in DNA, Sox factors are capable of bridging the gap between distal enhancers and proximal transcriptional elements, allowing for interaction between regulatory complexes separated by long distances in the genome (69). Furthermore, it has been demonstrated that the Sox HMG box has an adaptive tertiary structure, the formation of which is directed by DNA on binding consensus sequences (20, 97). The ability of the Sox HMG box to change tertiary structure, depending on DNA binding, has led to the proposal that single Sox factors are capable of bending DNA to different degrees in a context-dependent manner, facilitating differential transcriptional control of genes (101).

Functional Roles of Sox Factors Are Dependent on Spatial, Dose, and Temporal Context

Sox factors are expressed in nearly every tissue during embryogenesis and are emerging as a group of genes that are broadly expressed across a wide range of adult tissues as well. Individual Sox factors are expressed across many tissue and proliferating cell types, suggesting fundamental roles in cell maintenance. However, Sox factors exhibit some degree of cell and tissue specificity, in that they are expressed in multiple tissues, but not in every cell found in those tissues. For example, Sox9 is expressed in the Sertoli cells of the testis, in chondrocytes during cartilage formation, and in a subset of epithelial cells of the small intestine and colon (29, 38, 98, 107). This characteristic of expression patterns that are not restricted to one organ system or all cell types within tissues arising from the same germ layer suggests that Sox factors have a fundamental functional role in cell behavior across diverse tissue and cell types.

The ability to bind the same DNA sequence is predictive of redundancy between different Sox factors and the potential to functionally compensate for one another (27, 51). Compensatory mechanisms have been suggested by the observation that Sox5null and Sox6null mice each undergo chondrogenesis, but animals with deletions of both Sox5 and Sox6 fail to produce cartilage (83). These data imply that Sox5 and Sox6 are able to reciprocally compensate for one another and drive the development of cartilage.

Another important feature of Sox factors is that they can act in a dose-dependent manner. That is, varying levels of expression of a single Sox factor can elicit a variety of responses in distinct cell and tissue types. It has been suggested that gradients of endogenous expression of Sox factors across different cell types in a single tissue allow for different responses to the same exogenous signal (29, 30, 53, 91, 98). For example, data show that differing levels of Sox2 during development drive retinal tissue to adopt distinct phenotypes (91). Dose-dependent behavior of Sox factors was suggested for Sox9 in human patients suffering from campomelic dysplasia, a disorder defined by significant skeletal defects. It was observed that patients suffering from campomelic dysplasia in addition to sex reversal exhibited a varying range of phenotypic penetrance due to haploinsufficiency (30). Variable phenotypes, as opposed to a true wild-type vs. “knock-out” phenotypes, in campomelic dysplasia suggest that Sox factors are able to exert functional effects on gene expression in a dose-dependent manner.

In addition to behaving in a dose-dependent manner, Sox factors often exhibit temporal expression that may play an important role in the maintenance and differentiation of cellular lineages. The observed trend has been that the expression of Sox factors is maintained before cell fate decisions, then rapidly downregulated upon lineage commitment. This has been observed in the development of the testis, during which Sox9 and Sry undergo a change from upregulation to downregulation during precursor commitment to form Sertoli cells, as well as in dynamic expression patterns of Sox1-3 in neuroepithelial cell lineages (18, 32, 35, 51, 87, 95). Though still in the process of being thoroughly defined, the known transcriptional capabilities of Sox factors demonstrate that they are powerful regulators of cellular potency and developmental processes.

Sox17 Is Essential for GI Development

The epithelial layers lining the esophagus, stomach, and intestine, as well as a majority of liver and pancreatic tissue, all arise from the definitive endoderm during embryonic development (reviewed by Ref. 102). Sox17, a member of the SoxF subgroup, was shown to be essential to the development of definitive endoderm in mammals, as had previously been demonstrated for Sox17 orthologues in Xenopus (41, 45). Mice deficient in Sox17 showed defects in the definitive endoderm, beginning with endodermal induction. Specifically, there was an increase in apoptosis observed in the foregut, along with defects in cellular expansion in the mid- and hindgut, resulting in embryonic lethality at 10.5 days postcoitum (45). Recent studies have also demonstrated a role for Sox17 in the differentiation of human embryonic stem cells (HESCs). Overexpression of Sox17 in HESCs drove 78.51% of the cells to differentiate into definitive endoderm in the absence of cytokines, while treatment with activin A, a cytokine known to promote formation of definitive endoderm, only drove one-third of HESCs to differentiate similarly (77). Additionally, further manipulation with growth factors associated with lineage-specific differentiation was successful in inducing the expression of early hepatic and pancreatic markers in Sox17-overexpressing HESCs (77). Taken together, these findings highlight a critical role for Sox17 in the development of the mammalian GI tract. This established developmental role suggests that Sox factors are an important subject of study in the maintenance of stem cell populations in the organs of the adult GI tract.

THE UPPER GI TRACT: ESOPHAGUS/STOMACH

Maintenance and differentiation of cells in the upper GI tract are important in facilitating the developmental formation and continued function of the normal esophagus and stomach. Due to common embryonic origin of the esophagus and trachea, any aberrant molecular signaling early in development can result in phenotypes that compromise the integrity not only of the digestive tract, but that of the airway and respiratory system as well. In the adult organism, esophageal and gastric epithelial homeostasis is governed by maintenance and differentiation of resident stem and progenitor cells (46). Aberrant proliferation or differentiation in these cell populations can lead to metaplastic precancerous lesions that could ultimately result in functional deficits of the upper digestive tract. Therefore, an understanding of the regulatory factors governing development and maintenance of proper temporal and spatial cellular phenotypes within the upper GI tract is essential for the characterization of a wide range of disorders affecting the esophagus and stomach.

Stem Cells in the Esophagus

The esophageal epithelium is arranged in two layers: the basal layer, consisting of cuboidal epithelial cells, and the suprabasal layer, composed of polyhedral cells (54). Early research with radioactive thymidine-labeling studies demonstrated that cell division is restricted to the basal layer (54). These studies also demonstrated a relatively high rate of turnover in the esophageal epithelium, as nearly all of the basal epithelial cells were shown to divide in 3–5 days. More recent work has gone further to demonstrate that basal esophageal epithelial cells are arranged in clonal units (21, 92). Taken together, these data support the presence of an esophageal stem cell and stem cell niche in the basal layer of the esophageal epithelium. Furthermore, it has been shown that transit-amplifying progenitor cells generated by stem cells in the basal esophageal epithelium must enter the suprabasal layer before differentiating (21). This observation has led to the proposal that genetic changes must take place within progenitor cells before differentiation that allows them to generate appropriate cellular lineages once they enter the suprabasal layer (22). Significant genetic priming for differentiation suggests the involvement of potent transcriptional regulation, a functional requirement that makes Sox factors an attractive subject in esophageal stem cell biology.

Stem Cells in the Stomach

The human gastric epithelium consists of simple columnar epithelium and is divided into the cardia, fundus, and antrum (39). It is important to note that the murine stomach is divided differently, into forestomach, lined with stratified squamous epithelium, and hindstomach, lined with simple columnar epithelium (47). Invaginations, called gastric pits, line the gastric epithelium, each containing four or five gastric glands, which house the gastric epithelial proliferative zone (47, 55). In both fundic and antral gastric pits, gastric epithelial stem cells reside at the neck of the glands and drive proliferation bidirectionally up and down the gland (46). However, fundic and antral pits differ in terms of cell types generated by their respective stem cells and also in terms of rates of regeneration, with the antral pits driving cellular turnover at a greater rate than the fundic pits (36, 46, 68). This difference in proliferation across separate zones of the same tissue suggests differential genetic regulation of stemness in gastric epithelial stem cell populations. The demonstrated ability of Sox factors to regulate proliferative potential and stemness makes them attractive candidates for regulation of proliferation across the gastric epithelium.

Evidence That Sox Factors Play a Role in Stem Cell Physiology of the Upper GI Tract

During development, Sox factors drive tissue specification processes along the axis of the forming upper GI tract (73). The esophagus and stomach derive from the endodermal foregut and demonstrate similarities in terms of Sox expression. Of the Sox factors associated with the upper GI tract (Table 1), Sox17 is expressed in the esophagus and stomach, whereas Sox18 expression is reported in the stomach alone (50, 74). Within the normal GI tract, Sox2 shows expression in the esophagus and stomach, and its functional role in the upper GI tract has been extensively characterized (56, 73). Interest in the role of Sox2 in the stomach was originally driven by the observation that Sox2 expression is markedly downregulated in gastric carcinomas, implicating aberrant expression of the gene with a loss of proper cellular homeostasis (see Table 2) (56). This early observation suggested that Sox2 might also play a role in maintenance and differentiation processes of gastric stem cell populations.

Table 1.
Sox expression in embryonic and adult gastrointestinal (epithelium) tissue
Table 2.
Sox expression in gastrointestinal pathology and disease

Sox2 in the Development and Normal Biology of the Esophagus and Stomach

During early development of the esophagus, Sox2 is expressed in all cells of the endodermal foregut, but at embryonic day (E) 9.5 expression levels segregate in a dorsal-ventral manner that results in relatively high expression in the developing esophagus and relatively low expression in the developing trachea (73). Abnormal downregulation of Sox2 expression during embryogenesis was observed to result in esophageal atresia and tracheoesophageal fistula (TEF), with Sox2 protein undetectable at the site of TEF (67, 73). These data demonstrate that normal expression of Sox2 is required for appropriate tracheoesophageal morphogenesis.

In the case of murine gastric development, Sox2 levels are first expressed across the entire embryonic stomach to the duodenum, but decrease in the hindstomach, while remaining relatively high in the forestomach later in gestation (73). This gradient in expression levels is mirrored in adult human stomach, with Sox2 expression decreasing from fundus to antrum and becoming very low at the pyloric sphincter (93). The change in expression of Sox2 along the developing esophagus and stomach implies a dose-dependent role in the establishment of cellular fate, as high levels of Sox2 appear to specify an esophageal or gastric fate, whereas low levels of Sox2 appear to drive adaptation of tracheal or intestinal fates.

Sox2 plays an important role in cellular differentiation processes that establish the structure of epithelia formed along the length of the upper GI tract (73). It has been proposed that high levels of Sox2 during murine development drive the formation of stratified, squamous epithelium, while low levels direct cell fate toward columnar epithelium (67). The change in mucosal structure from stratified squamous epithelium in the murine forestomach to columnar epithelium in the hindstomach supports this concept. Furthermore, mice exhibiting TEF concurrent with decreased levels of Sox2 expression exhibit ectopic columnar epithelium at the site of TEF, in contrast to wild-type littermates, which have physiologically normal squamous epithelium throughout the esophagus (67). In addition to playing a role in the development of the structural anatomy of the upper GI tract, Sox2 appears to be important in the establishment of proper epithelial subtypes along the esophageal-gastric axis.

Roles for Sox2 in Precancerous and Cancerous Lesions of the Esophagus and Stomach

Cellular changes in precancerous and cancerous lesions of the esophagus and stomach suggest that Sox2 may also play an active role in the maintenance and differentiation of cells in adult tissues of the upper GI tract. Sox2 appears to be important for maintaining a gastric phenotype in epithelial cells in the stomach (73, 90, 93). Failure to maintain gastric phenotype in gastric epithelial cell populations can lead to intestinal metaplasia (IM), or the precancerous conversion of gastric epithelial cells to intestinal epithelial cells (93). Studies of human tissue from patients suffering from IM showed that Sox2 is progressively downregulated throughout progression from normal gastric epithelium to widespread IM (93). A loss of Sox2 was also observed in both a rat model of IM and samples from human cases of Barrett's esophagus (4). These observations are strikingly similar to the finding that segregation of tissue expressing Sox2 from tissue not expressing Sox2 early in development coincides with the formation of a gastric-duodenal junction (67). Taken together, these studies suggest that Sox2 is critical in maintaining a distinct boundary between the epithelia of the esophagus and stomach and intestinal epithelia.

Sox2 expression levels have also been shown to associate with other distinct markers of a gastric phenotype. For example, Sox2 upregulates the expression of the stomach-specific pepsin precursor pepsinogen A in gastric cell lines, as well as ectopically in colon cancer cell lines (90). Conversely, interference with Sox2 expression causes a significant decrease in pepsinogen A, suggesting a pivotal role for Sox2 in pepsinogen A expression (90). Further evidence for Sox2 maintenance of a gastric phenotype is found by comparing expression of gastric-specific mucins vs. that of the intestinal-specific mucin. When Sox2 levels decrease, there is a progression from normal gastric phenotype to IM, and expression of gastric-specific mucin decreases, while levels of intestinal-specific mucin increase (93). To summarize these studies, high levels of Sox2 are associated with the upregulation of markers for differentiation specific to the gastric epithelium, whereas decreasing levels of Sox2 correlate with the upregulation of a lineage-specific marker normally restricted to the intestinal epithelium.

Gastric cancer is commonly associated with a downregulation of Sox2 (56). It has been proposed that methylation and epigenetic silencing of Sox2 in gastric cancer leads to progressively aberrant proliferation of the gastric epithelium, an idea supported by the clinical observation that patients presenting with gastric carcinomas that exhibit methylation of the Sox2 gene face poorer prognoses than those without Sox2 methylation (67). Reinforcing the idea that Sox2 might play a tumor-suppressive role in the gastric epithelium is the observation that exogenous overexpression of Sox2 has an inhibitory effect on proliferation of gastric carcinoma cells in vitro, an effect that progresses to morphological change and apoptosis with persistent overexpression of Sox2 (67). Interestingly, a recent study on human esophageal squamous cell carcinoma reported that 15% of patients had amplification of Sox2 in tissue samples from this tumor type (12). This study raises the possibility that Sox2 may play a different regulatory role in the esophagus than it does in the stomach. Taken as a whole, the above data suggest that Sox2 is a critical player in the maintenance of a gastric epithelial cellular phenotype, as well as a regulator of normal proliferation of the esophageal and gastric epithelia.

LOWER GI TRACT

The lower GI tract, which includes the small intestine and colon, functions to absorb nutrients in the digestive tract through a complex interaction between epithelial, vascular, nervous, and lymphatic tissues. In addition, epithelial tissue lining the luminal surfaces of the lower GI tract must be specialized for absorptive function, while simultaneously maintaining a barrier against the bacteria-rich digestive lumen to preserve the sterility of the rest of the body. A majority of epithelial cells carry out highly specialized functions in the intestinal and colonic epithelia and undergo rapid turnover rates that result in replacement of nearly the entire epithelium every 7 days (108). This rate of rapid renewal, combined with the need to sustain physiological and cellular homeostasis, emphasizes the importance of regulation of cellular maintenance and differentiation in the small intestine and colon. The intestinal epithelium has been an attractive target for the study of cellular maintenance and differentiation, especially in terms of potent mitogenic signaling via the Wnt pathway. The role of the intestinal and colonic epithelia in inflammatory bowel disease, as well as high rates of colon cancer, has fueled a long-standing interest in maintenance and differentiation of this tissue type.

Stem Cells of the Small Intestine and Colon

The proliferative region of the intestinal and colonic epithelia has long been known to reside in the crypts of Lieberkuhn (1315). Division of multipotent stem cells and differentiation of progenitor cell populations in the crypts drives the replacement of terminally differentiated cells on the villi. These cells are then sloughed into the lumen, facilitating epithelial renewal. In addition to generating absorptive enterocytes that comprise a majority of the terminally differentiated epithelium, the intestinal epithelial stem cells also give rise to secretory lineages that include goblet and enteroendocrine cells in the small intestine and colon, as well as Paneth cells, which are restricted to the small intestine (1316). Strong evidence points to the Wnt/β-catenin pathway as a key mitogenic signaling cascade driving crypt proliferation (17). Significantly less is understood in terms of how Wnt/β-catenin signaling is regulated to elicit appropriate and distinct responses from cells responsible for controlling stem cell maintenance vs. differentiation in the small intestine and colonic epithelia. Recent advances in the understanding of Sox function in the intestinal epithelium has revealed that this family of transcription factors plays an important role in the downstream regulation of Wnt activity (52).

High rates of proliferation, differentiation, and cell turnover make the intestinal epithelium a useful model system to study the role of Sox factors in regulating cellular homeostasis in the GI tract. Screening for mRNA has revealed expression of Sox2, Sox3, Sox4, Sox5, Sox6, Sox7, Sox9, Sox10, Sox11, Sox17, and Sox18 in whole small intestine and colon (see Table 1). A caveat concerning mRNA expression is that some data are reported from whole tissue analysis. Therefore, some Sox factors reported to be expressed in the intestine might be specific to nonepithelial cell types, such as smooth muscle and enteric nerve cells, which will not be addressed in this review. However, the role of Sox9 in the epithelium of the lower GI tract has been extensively characterized (5, 6, 82). Studies utilizing the intestine as a model system have been instrumental in revealing important epithelial roles for Sox4 and Sox17 as well (82). Data suggest that Sox factors contribute to the proper regulation of the proliferative cell populations in the intestinal and colonic epithelium.

Sox9 Regulates Proliferation in the Small Intestine and Colon

The most extensively studied Sox factor in the intestinal epithelium is Sox9, which has been shown to be primarily expressed in the stem/progenitor region of the crypts in the small intestine and colon, with some limited expression observed in cells throughout the villi of the small intestine (6, 29, 44). The localization of Sox9 to the proliferative compartment of the intestinal epithelium supported a possible involvement in the Wnt/β-catenin pathway, as Wnt is known to drive proliferation in the crypts. Disruption of Wnt signaling in early postnatal stages was shown to completely ablate Sox9 expression in the intestinal and colonic epithelia, identifying Sox9 as a downstream target of Wnt (6).

Other studies demonstrate that Sox9 plays an important role in the regulation of cell fate and differentiation. Sox9 expression has been shown to prevent cellular differentiation into mucin 2-expressing goblet cells in vitro, implicating Sox9 in the maintenance of a nondifferentiated population of putative stem/progenitor cells (6). Furthermore, Sox9 was shown to repress genes associated with terminally differentiated cell types, including CDX2 in intestinal epithelium and carcinoembryonic antigen (CEA) in colonic epithelium, in vitro (6, 44). More recently, conditional embryonic Sox9 knockout mice were shown to lack Paneth cells in the intestinal epithelium following birth (5, 64). Taken together, these data suggest that Sox9 plays a complex regulatory role in cell fate decisions and differentiation downstream of Wnt.

Findings suggestive of Sox9 association with a nondifferentiated pool of cells located in the classical “stem cell niche” of the intestinal and colonic epithelia provide evidence that Sox9 might also play a role in the maintenance of a stem/progenitor phenotype. However, given the multitude of proposed functional roles for Sox9, it can become conceptually difficult to grasp how a single gene appropriately regulates different cellular responses across the epithelium. Sox9 is expressed at variable levels in the intestinal epithelium, and these levels have been shown to correlate with different cellular phenotypes, reinforcing earlier observations that Sox factors function in dose-dependent manners (29). Specifically, recent studies utilizing a bacterial artificial chromosome transgenic mouse model, in which regulatory elements of Sox9 drive the expression of enhanced green fluorescent protein, classified Sox9 expression as “sublow,” “low,” and “high” (29, 33). Sox9 high-expressing cells were demonstrated to be fully differentiated enteroendocrine cells, as well as the only Sox9-positive cell type observed in villi, whereas Sox9 low-expressing cells were shown to correlate with increased expression of established functional markers of intestinal epithelial stem cells (29). Recently, it was shown that Sox9 low-expressing cells are multipotent and self-renewing in vitro and that Sox9 sublow-expressing cells are enriched for markers of proliferation, as well as early markers of differentiation, suggesting that Sox9 sublow expression corresponds to the transit-amplifying cells of the intestinal epithelium (33). In vitro studies have shown that Sox9 inhibits the transcription of cMyc and cyclin D1 by β-catenin/T-cell factor, suggesting that Sox9 might regulate Wnt signaling via a dose-dependent negative feedback loop (5, 6, 29). One model proposes that Sox9 has a dose-dependent, inverse relationship with proliferative potential in response to Wnt signaling in the intestinal crypts (29). This proposal is strongly reinforced by the identification of the Sox9 sublow-expressing putative transit amplifying population, wherein very low levels of Sox9 would be expected to result in an upregulation of cMyc and cyclin D1 in response to Wnt signals, potentiating the rapid proliferation needed to constantly renew the terminally differentiated cells of the intestinal epithelium (33). Interestingly, very high levels of Sox9 are expressed in the enteroendocrine populations, which develop in the absence of Wnt-signaling (29, 100). This observation implicates a Wnt-independent regulatory role for Sox9 in postmitotic cell populations.

Sox9 and Colon Cancer

In addition to apparent regulatory roles in the normal biology of the small intestine and colon, increased expression of Sox9 has been noted in colon cancer (see Table 2). Screening of several human colon cancer cell lines revealed that Sox9 mRNA and protein were upregulated over controls (see Table 3) (6). Immunohistochemistry of serial sections of human adenocarcinomatous colon also demonstrated upregulated expression of Sox9 protein in an ectopic pattern that colocalized with increased nuclear localization of β-catenin (6). Upon first inspection, these data appear to be in direct conflict with the observation that low levels of Sox9 might maintain a nondifferentiated cellular phenotype, as overexpression of Sox9 in nontransformed small intestine cell lines or colon cancer cell lines decreases proliferation and prevents differentiation into both secretory and absorptive lineages (29, 44). However, mRNA analysis of whole tissues and cell lines does not account for the level of Sox9 expression in individual cells, which is of critical importance due to the dose-dependent behavior of Sox factors. A tumor expressing higher levels of Sox9 mRNA might do so because there is an increase in the number of Sox9 low stem cells and Sox9 sublow progenitor cells over negative controls. In this case, there would be an increase in absolute mRNA levels of Sox9 due to ectopic cellular expression that does not necessarily indicate an increase in Sox9 expression in cells that express the gene under normal conditions.

Table 3.
Sox expression in cell lines derived from gastrointestinal tissue

In addition, downregulation of Sox9 was shown to be sufficient to allow increased expression of CEA in colonic adenocarcinomas in vitro, while overexpression of Sox9 was sufficient to prevent expression of CEA in the same cell lines (44). The observation that Sox9 regulates CEA expression by colonic adenocarcinomas in vitro is clinically relevant, as CEA is associated with antiapoptotic effects in colon cancer that can lead to metastasis (66, 105).

Jay et al. (44) hypothesized that Sox9 might have proapoptotic effects in colonic adenocarcinoma and demonstrated that induced expression of Sox9 leads to an increase in apoptosis in colon cancer cell lines in vitro. These data supported the prior association of CEA with decreased apoptosis and the authors' demonstration of the ability of Sox9 to indirectly inhibit the CEA promoter, leading to the conclusion that regulation of Sox9 might be an attractive approach to mediating antiapoptotic effects of CEA in aggressive colon cancers (44, 105). A mouse model exhibiting Sox9-knockout specific to the intestinal epithelium revealed a significant change in colonic epithelial morphology, with pronounced crypt hyperplasia and the formation of atypical, “villus-like” structures protruding into the lumen (5). Supporting previous observations that Sox9 might play a proapoptotic role in colon cancer, Sox9 knockout mice exhibited a high rate of spontaneous microadenoma formation (5). These emerging data regarding roles of Sox9 in colon cancer suggest that the gene is not only important in the development and progression of tumors, but might also be exploited toward diagnostic and therapeutic ends.

Preliminary Evidence Suggests Roles for Sox4 and Sox17 in the Small Intestine and Colon

In addition to Sox9, limited yet intriguing evidence has emerged that suggests other Sox factors also have important regulatory roles in maintenance and differentiation in the intestinal epithelium. Interestingly, like Sox9, Sox4 and Sox17 have both been shown to differentially regulate β-catenin activity in colon cancer in vitro, leading to changes in cellular proliferation (50, 82). It was found that Sox17 is downregulated in spontaneous adenomas of APC-min mice, while Sox4 is upregulated (82). Expression analysis was supported by data revealing that forced expression of Sox17 in colon carcinoma cells resulted in a downregulation of β-catenin/T-cell factor activity and a decrease in proliferation, while Sox4 overexpression had the opposite effect (50, 82). These data show that individual Sox factors differentially regulate intestinal epithelial proliferation and suggest different ratios of Sox factors in the same cell may work in concert to control proliferation. Furthermore, the observation that both Sox9 and Sox17 negatively regulate Wnt activity is suggestive of overlapping roles for Sox factors in the intestinal epithelium.

PANCREAS

The study of pancreatic development and cellular homeostasis is arguably one of the most dedicated efforts to translate basic cell biology to clinically applicable therapies. The pancreas resides at an epicenter of questions concerning both individual quality of life and public health issues, as both type 1 and type 2 diabetes present with significant comorbidity at increasingly high rates in the general population and are projected to affect 366 million individuals globally by 2030 (103). Of special interest is the idea that clinical replacement of absent or dysfunctional β-islet cells could greatly reduce the wide-sweeping impact of diabetes on the healthcare system as a whole.

Stem Cells in the Pancreas

The pancreas is a complex organ that fulfills both exocrine and endocrine functions. A majority of the pancreas is dedicated to exocrine function, producing enzymes essential for the digestion of macronutrients. The functional unit of the endocrine pancreas comprises specialized endocrine cells in the islets of Langerhans, which are interspersed throughout the exocrine pancreas. The islets consist of ε-cells (glucagon secreting), β-cells (insulin secreting), δ-cells (somatostatin secreting), ε-cells (ghrelin secreting), and PP-cells (pancreatic polypeptide secreting). The regulation of pancreatic endocrine cell behavior is vital for homeostasis of the organism and an integral component in the pathogenesis of diabetes. As such, a great deal of attention has been devoted to understanding putative stem cell populations within the adult pancreas. To date, the precise location of pancreatic stem cells remains debated, but evidence suggests that ductal, acinar, and islet cells are capable of contributing to pancreatic regeneration (reviewed by Ref. 8). Strikingly, recent evidence has also shown that mature β-cells are capable of driving β-cell regeneration under both normal conditions and following injury (25, 65). The ability to modify proliferation strategies either intrinsically or in response to extrinsic signaling is suggestive of complex and context-specific transcriptional regulation of putative stem cell populations in the pancreas.

Sox factors have been an attractive target of research in pancreatic physiology and disease due to their ability to modulate the proliferative capacity of stem and progenitor cells. In terms of organs of the GI tract, the breadth of Sox factors known to be expressed in the pancreas is rivaled only by that expressed in the intestine. Many Sox genes have been localized to the pancreas, including Sox4, Sox6, Sox9, and Sox13 (see Table 1) (43, 48, 79, 104). Sox4, Sox6, Sox9, and Sox13 are especially noteworthy in that they have been shown to have functional roles in pancreatic physiology. By contrast, the current knowledge of other Sox factors in the pancreas is restricted to expression analysis data, with no clear functional roles yet determined. This discussion of Sox factors in the pancreas will, therefore, focus on evidence for functional roles of Sox expression in the maintenance and differentiation of pancreatic cell populations.

Sox9 in Pancreatic Development

Sox expression in the developing pancreas is dynamic, with gene expression patterns and levels changing over the course of development. Sox9, the most studied Sox factor in the pancreas, has been shown to exhibit dynamic expression throughout ontogeny. During murine development, Sox9 undergoes changes in expression level that span broad expression at E9.5 to restricted, downregulated expression by late gestation (57). Spatial expression of Sox9 has been shown to associate with the entire pancreatic epithelium at E10.5–E12.5, but at late gestation is restricted mostly to the islets of Langerhans (57, 79). Lineage-tracing studies have shown that cells expressing Sox9 in the embryonic pancreas colocalize with multipotent progenitor cells that give rise to the pancreatic endocrine lineages, as well as to early pancreatic exocrine progenitors (78). These data show that Sox9 marks a population of cells that give rise to all pancreatic cell types.

Sox4 shows similar changes in expression across pancreatic development, as it is expressed at high levels early in development and undergoes downregulation between E12.5 and E15.5, but exhibits subsequent, slight upregulation in adult islets (57, 79). These studies support the notion that dynamic changes in Sox factor expression are a common theme in normal pancreatic development and suggest that Sox factors may regulate the timing of specific processes within the developmental timeframe.

Gene knockout experiments resulting in pancreas-specific ablation of Sox9 in mice have demonstrated that Sox9 is essential to pancreatic development, as knockout mutants died shortly after birth due to dehydration and elevated blood glucose levels and displayed severely abnormal gross pancreatic morphology (79). In addition, pancreas-specific Sox9 knockout mice exhibited heterogeneous phenotypes, with either a complete absence of pancreatic endocrine cells or only sporadic representations of these cell types, suggesting that Sox9 plays a critical role in the cellular development of the endocrine pancreas (79). Heterozygous mutants for pancreas-specific Sox9 deficiency are viable and fertile and exhibit normal gross pancreatic morphology. Interestingly, on histological examination, heterozygous mutants are shown to have significantly reduced numbers of pancreatic endocrine cells that are functionally normal in terms of mRNA expression of insulin processing enzymes and insulin secretion (78). These data suggest that, while Sox9 is important in terms of gross pancreatic development and early differentiation of pancreatic endocrine lineages, it is not essential for normal function of endocrine cells once they have undergone cell fate decisions. Furthermore, the authors note that varying degrees of deficit observed between haploinsufficiency and complete knockout are indicative of a dose-dependent role of Sox9 in the endocrine pancreas (78). This notion is further supported by the observation that haploinsufficiency of Sox9 in human patients suffering from campomelic dysplasia results in abnormal islet cell morphology (70).

Sox4 in Pancreatic Development

Similar to Sox9, expression patterns of Sox4 are broad across pancreatic buds in early pancreatic development and restricted to the endocrine cells of the islets by adulthood (57, 104). Interestingly, observations regarding functional effects of Sox4 have been very similar to those made for Sox9. Due to embryonic lethal cardiac defects in homozygous Sox4null mutants, all experiments examining pancreatic roles of Sox4 past E11.5 were conducted ex vivo on explant cultures from mutant embryos (76, 104). There was no observed difference in growth rate between wild-type, heterozygous, and homozygous Sox4-deficient explant cultures. Further examination revealed that heterozygous mutant and wild-type cultures were able to generate islet cells in vitro that expressed insulin and glucagon, where homozygous mutants were not (76, 104). However, islet cells from Sox4 homozygous knockout mice continued to exhibit normal markers of endocrine cell lineages, albeit at lower expression levels relative to heterozygous mutant and wild-type explant cultures (76, 104). Decreased endocrine cell differentiation in Sox4null explant cultures suggests that Sox4 plays a regulatory role in the expansion of the pancreatic endocrine compartment.

Possible functional roles of Sox4 and Sox9 in terms of regulating the cellular population of the endocrine pancreas are similar in that both seem to contribute to pancreatic cell number during development without affecting normal endocrine functions in cells that are able to properly differentiate. Wilson et al. conclude that Sox4, like Sox9, is a requisite component of normal endocrine expansion in the developing pancreas (104). The similarities between observed functional roles of pancreatic Sox4 and Sox9 suggest that the two might play similar roles in the genesis of pancreatic endocrine cells. The regulation of pancreatic endocrine differentiation by Sox4 and Sox9 represents an area of research that warrants further investigation.

Sox6 Is Associated With Hyperinsulinemia

In terms of functional maintenance of the adult pancreatic phenotype, Sox6 is emerging as a potentially powerful mediator of gene regulation and cellular maintenance in pancreatic β-cells. Interest in pancreatic Sox6 is supported by observations that persistent downregulation of Sox6 is strongly associated with hyperinsulinemia in obese mice (42). Furthermore, downregulation of Sox6 coincident with hyperinsulinemia was correlated with high-fat diet treatments in normal mice, as well as genetic defects leading to obesity (42). These data implicate Sox6 in the dysregulation of insulin signaling associated with type 2 diabetes mellitus. Whereas Sox6 is shown to localize to normal adult β-cells and suppress genes implicated in β-cell proliferation, downregulation of Sox6 has been shown to reduce this suppression and lead to an increase in glucose-stimulated insulin secretion (42). Furthermore, a reduction in levels of Sox6 leads to proliferation and expansion of β-cell populations. Immunoprecipitation assays suggest that Sox6 inhibits proliferation by forming complexes with β-catenin and serves as a cofactor for histone modifications that suppress downstream activities of β-catenin (43). Interestingly, a recent study utilizing bivariate genomewide association study examination of polymorphisms present in obesity and osteoporosis in human males indicated that Sox6 is strongly associated with both increased body mass index and decreased bone mineral density (58). These data would suggest that Sox6 plays roles in both obesity-associated insulin regulation, as well as regulation of β-cell proliferation in the adult pancreas.

Sox13 Is a Diabetes-associated Autoantigen

Sox13 is expressed throughout pancreatic development and in adult islet cells and has been implicated in functional deficiencies in β-islet cells in type 1 diabetes mellitus (48, 57, 104). Surveys of type 1 and type 2 diabetes patients, as well as control subjects, demonstrated a higher occurrence of Sox13 autoantigens in the diabetic population (48). Furthermore, Sox13 autoantigens were significantly upregulated in type 1 patients compared with patients with type 2 diabetes (48). While these data demonstrate a strong correlation to autoimmune-associated type 1 diabetes, the authors are careful to point out that no definitive conclusions can be reached as to whether or not Sox13 autoantigens are causative of, or consequential to, type 1 diabetes.

Sox2 Plays a Role in the Development of Pancreatic Cancer

In addition to roles in development and maintenance of pancreatic cellular phenotypes, Sox factors have been implicated in aberrant signaling processes leading to pancreatic cancer. As previously described in regards to gastric cancer, Sox2 is also associated with abnormal cell types observed in pancreatic intraepithelial neoplasia (PanIN). Observations that Sox2 is upregulated in PanIN correlate with the observed upregulation of extrapancreatic epithelial markers (72). Sox2 has been shown to be essential for the maintenance of gastric epithelial phenotypes, and abnormal expression of Sox2 is associated with the development of gastric cancers through the failure to maintain this phenotype (67). Interestingly, levels of Sox2 in PanIN are upregulated over normal pancreatic expression levels to levels normally seen in the gastric fundus and antrum (72). This, along with the identification of pepsinogen C and the gastric-specific mucin Muc6 in PanIN, suggests that upregulation of Sox2 in PanIN drives pancreatic cells to adopt an abnormal gastric epithelial phenotype (72). These studies continue to underscore the spatiotemporal and dose-dependent roles of Sox family transcription factors in maintenance and differentiation processes in the GI tract.

HEPATOBILIARY SYSTEM

The hepatobiliary system, which consists of the liver, gallbladder, and bile ducts, plays a central role in proper function of the GI tract. The liver serves a wide range of functions essential for both digestion and overall metabolism, acting as an exocrine organ, as well as a filter for the systemic circulation. Homeostasis within hepatocyte populations, the functional parenchymal cells of the liver, is essential for proper hepatobiliary function and homeostasis of the entire organism. Pathologies resulting in insufficient or aberrantly upregulated expansion of hepatocytes, such as cirrhosis or hepatocellular carcinoma, respectively, present clinical problems, as well as significant losses in quality of life for patients.

Stem Cells of the Hepatobiliary System

The liver is compromised of individual functional units called hepatic lobules. Each lobule contains a portal triad consisting of a portal vein, hepatic artery, and bile duct, as well as hepatocytes, which are organized into rows called hepatic plates. Blood flows from the portal vein past the hepatocytes, which interact with the venous blood via a special fenestrated endothelium. After flowing past the hepatic plates, blood drains into the central vein, located opposite of the portal triad in the hepatic lobule (60). Normal hepatocyte turnover is slow, with hepatocyte lifespan having been calculated at ~200–300 days (11). Despite this low basal rate of turnover, the liver demonstrates remarkable regenerative characteristics following substantial loss of cells, as in the case of partial hepatectomy. In rats, the liver has been observed to regenerate and regain its original cell number in just 3–4 days following partial hepatectomy (10, 86). The rapid rate of regeneration lends itself to clinical benefit in liver transplantation, as it facilitates the use of living donors. Interestingly, radioactive thymidine-labeling studies have demonstrated that this tissue-regenerative process is driven by mature hepatocytes (10, 86). Stem cell populations in the liver do not appear to make significant contributions to regeneration, except in cases in which hepatocytes are damaged, such as following the administration of toxic pharmacological agents in animal models (26). When hepatocytes are significantly damaged, their regeneration appears to be dependent on a hepatic stem cell population. Progenitor cells of the liver, termed “oval cells,” are derived from a nonhepatocyte precursor and are classically viewed as bipotential progenitors, capable of giving rise to both hepatic and biliary epithelial cells (1, 99). The ability to undergo fate decisions between hepatic and biliary lineages is indicative of precise transcriptional regulation of genes controlling differentiation processes in hepatobiliary progenitor populations.

In addition, complex regenerative strategies of the liver suggest powerful molecular regulatory mechanisms that are capable of controlling regeneration differentially in homeostatic and pathological states. Hepatocyte contribution to cellular regeneration following partial hepatectomy represents a scenario in which tight control of proliferative capacity would be essential to trigger mature cells to divide but also prevent aberrant growth once proper cell number was restored. The proven ability of Sox factors to regulate “stemness” in other tissues makes their potential roles in hepatobiliary stem and progenitor cell populations especially interesting. However, despite an increasingly detailed understanding of hepatic regeneration, the role of Sox factors in the hepatobiliary system remains poorly understood. Early research has revealed basic roles and produced expression data for a handful of Sox factors in the hepatobiliary system, including Sox9 and Sox17 (see Table 1). However, no single Sox factor has emerged as being central to hepatobiliary stem cell populations.

Sox9 and Sox17 Contribute to Biliary Development

Recent research has begun to define emerging roles for Sox9 and Sox17 in the development of biliary ducts (3, 94). Biliary tubulogenesis proceeds via a two-step process, starting first with the differentiation of hepatoblasts into cholangiocytes, followed by ductal morphogenesis, with cellular asymmetry (hepatoblasts vs. cholangiocytes) between the parenchymal and portal regions of the developing duct maintained throughout tubulogenesis (3). Throughout the process of tubulogenesis, Sox9 is preferentially expressed on the portal/biliary side of the developing duct, with no apparent expression in the parenchymal/liver region from E10.5 onward. Postnatal expression of Sox9 was found to be restricted to small ducts of the biliary system (3). Interestingly, liver-specific knockout of Sox9 driven by Alfp-Cre did not result in aberrant biliary duct formation. Rather, Sox9 knockout animals developed normal biliary ducts, but at a significantly slower rate than wild-type animals. Furthermore, Sox9 was found to regulate the expression of other genes implicated in development, including genes in the Notch and transforming growth factor-β pathways (3). These data demonstrate that Sox9 plays a critical role in the timing of biliary tubulogenesis, but also suggest that other compensatory mechanisms or signaling pathways exist that ultimately make Sox9 nonessential for biliary duct development.

In contrast to Sox9, recent data suggest that Sox17 is required for biliary development, specifically for the development of the gallbladder. Expressed throughout the foregut endoderm early in development, Sox17 later becomes restricted to the gallbladder region of the foregut, between the hepatic and pancreatic buds (94). Interestingly, early expression of Sox17 overlaps with markers for pancreatic fate, but, with biliary induction later in development, Sox17 is preferentially expressed in biliary primordium only (85). Tissue-specific knockout of Sox17 results in improper positioning of the endoderm, consequently not only causing a lack of gallbladder development, but also resulting in ectopic development of pancreatic cells in the anatomic location of the gallbladder (85, 94). Conversely, continued expression of Sox17 throughout development in cells also expressing early pancreatic markers resulted in the suppression of pancreatic development (85). These data demonstrate that Sox17 is essential for the segregation and development of biliary primordium from early foregut cells that give rise to both pancreatic and biliary cells. Sox17, therefore, appears to play an important role in fate specification during gallbladder and pancreatic development in the hepatobiliary system.

Preliminary Findings Point to Wider Roles for Sox Factors in the Hepatobiliary System

Aside from data generated by emerging biliary developmental research, Sox factors remain mostly uncharacterized in the hepatobiliary system, especially in terms of possible roles in hepatoblast maintenance and differentiation in the liver. Sox2 has been shown to be upregulated in Hep-12 cells, while Sox7 and Sox17 have been overexpressed in HESCs to drive differentiation toward hepatic-like phenotypes in vitro, but functional roles of these Sox factors in normal hepatic development and hepatoblast maintenance remain undefined (77, 109). Additionally, Sox13 has been identified as an autoantigen in primary biliary cirrhosis, while Sox2 is upregulated in tumors of the ampulla of vater (28, 75). Despite these findings, Sox factors in general are poorly described in pathogenesis in the hepatobiliary system. Data supporting powerful regulatory roles of Sox factors in stem cell populations of other GI tissues suggest that the role of Sox factors in the liver is an area deserving of further investigation.

CONCLUSION

Diseases related to maintenance and differentiation of cells within the GI tract, such as diabetes, colon cancer, and cirrhosis, affect a significant portion of the general population and often cause physiological consequences that negatively impact quality of life for affected individuals. An emerging understanding of tissue-specific stem cells holds significant promise toward the development of the next generation of advanced clinical therapies, but the understanding of molecular regulation of these stem cells remains rudimentary. Initial studies have identified Sox factors as key players in the processes of stem cell maintenance and differentiation across nearly all organ systems in the GI tract.

Sox factors possess attractive functional capabilities that allow them to serve as versatile and powerful regulators of transcriptional activity. To date, multidisciplinary research has yielded sufficient data to reach general conclusions concerning members of the Sox family of genes. In simplest terms, the Sox family is made up of genes that behave as classical transcription factors, but also have the ability to affect dramatic conformational changes through DNA bending. The ability to physically alter the shape of DNA has the potential to allow for the joining of distal enhancing elements with proximal transcriptional machinery, as well as allow for inhibitory effects.

Sox factors are attractive from a research standpoint in adult tissue due to their broad expression patterns, implication in maintenance of stem cell populations, and context-dependent functional roles. In large organ systems, such as the GI tract, Sox factors have the potential to reveal unifying themes across organs that are functionally dissimilar, but derived from the same germ layer. Additionally, the feature of dose-dependent behavior might allow Sox factors to differentially modulate transcriptional responses to mitogenic signals, regulating proliferative potential in stem and progenitor cell populations.

From a translational standpoint, the ability to identify and manipulate cell populations via Sox function could lead to the directed control of stem cell populations in vivo. Additionally, understanding Sox function could allow for the in vitro expansion and autologous transplantation of GI cells and tissues, a long-standing therapeutic ideal of stem cell research. Dose-dependency and redundancy might allow Sox factors to be exploited in a manner that allows for the “fine-tuning” of healthy and diseased cells at the genetic level.

Despite recent advances in functional characterization of Sox factors, many important questions regarding the roles of specific Sox genes in the GI tract remain. One significant area that merits increased investigation is the expression and role of Sox factors in hepatobiliary physiology. While members of the Sox family have been used to mark a hepatic lineage in embryonic stem cell differentiation studies and described in terms of hepatic angiogenesis, no data exist describing possible roles for Sox in terms of hepatocyte function and proliferation (62, 85). Additionally, the ability of Sox factors to dramatically bend DNA warrants further investigation toward the functional role of Sox-mediated structural and higher order genomic changes in stem cell populations. The elucidation of transcriptional roles for Sox factors might be limited by conventional genetic assays. Standard techniques employed to detect direct downstream targets of transcription factors in proximal promoter regions could theoretically prove inefficient in detecting distal Sox target genes that are activated through DNA bending and, therefore, not amenable to this form of detection. The development of novel technical approaches to overcome this obstacle is vital to the further study of Sox factors and their role in stem cell populations. Evidence to date and the potential for translational application strongly support further investigation into the role of Sox factors in tissue-specific stem cell populations of the GI tract.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

ACKNOWLEDGMENTS

We thank Drs. P. Kay Lund, Susan Henning, Christopher Dekaney, and Victoria Bali for useful discussions. We also acknowledge Kyle Roche and Michael Cronce for helpful comments. Work in Dr. Magness' laboratory was supported by National Institutes of Health, 1-K01-DK080181-01, NIH R03 DK089126-01, and the North Carolina Biotechnology Center Grant.

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