Expression Pattern Of Sox9 Research Articles

Down-regulation of Fibulin-5 is associated with aortic dilation: role of inflammation and epigenetics.

Destructive remodelling of extracellular matrix (ECM) and inflammation lead to dilation and ultimately abdominal aortic aneurysm (AAA). Fibulin-5 (FBLN5) mediates cell-ECM interactions and elastic fibre assembly and is critical for ECM remodelling. We aimed to characterize FBLN5 regulation in human AAA and analyse the underlying mechanisms. FBLN5 expression was significantly decreased in human aneurysmatic aortas compared with healthy vessels. Local FBLN5 knockdown promoted aortic dilation and enhanced vascular expression of inflammatory markers in Ang II-infused C57BL/6J mice. Inflammatory stimuli down-regulated FBLN5 expression and transcriptional activity in human aortic vascular smooth muscle cells (VSMC). Further, aortic FBLN5 expression was reduced in LPS-challenged mice. A SOX response element was critical for FBLN5 promoter activity. The SOX9 expression pattern in human AAA parallels that of FBLN5, and like FBLN5, it was reduced in TNFα-stimulated VSMC. Interestingly, SOX9 over-expression prevented the cytokine-mediated reduction of FBLN5 expression and transcription. The inhibition of Class I histone deacetylases (HDACs) by MS-275 or gene silencing attenuated the inflammation-mediated decrease of FBLN5 expression in VSMC and in the vascular wall. Consistently, HDAC inhibition counteracted the reduction of SOX9 expression induced by inflammatory stimuli and prevented the TNFα-mediated decrease in the binding of SOX9 to FBLN5 promoter normalizing FBLN5 expression. We evidence the deregulation of FBLN5 in human AAA and identify a SOX9/HDAC-dependent mechanism involved in the down-regulation of FBLN5 by inflammation. HDAC inhibitors or pharmacological approaches that aimed to preserve FBLN5 could be useful to prevent the disorganization of ECM induced by inflammation in AAA.

Lineage tracing of Sox2-expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti

The transcription factor Sox2 is both necessary and sufficient for the generation of sensory regions of the inner ear. It regulates expression of the Notch ligand Jag1 in prosensory progenitors, which signal to neighboring cells to up-regulate Sox2 and sustain prosensory identity. However, the expression pattern of Sox2 in the early inner ear is very broad, suggesting that Sox2-expressing progenitors form a wide variety of cell types in addition to generating the sensory regions of the ear. We used Sox2-CreER mice to follow the fates of Sox2-expressing cells at different stages in ear development. We find that Sox2-expressing cells in the early otocyst give rise to large numbers of non-sensory structures throughout the inner ear, and that Sox2 only becomes a truly prosensory marker at embryonic day (E)11.5. Our fate map reveals the organ of Corti derives from a central domain on the medial side of the otocyst and shows that a significant amount of the organ of Corti derives from a Sox2-negative population in this region.

Clinical implication of Sox9 and activated Akt expression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most leading causes of cancer-related death. Cancer stem cell is responsible for tumor initiation, metastasis and relapse. Sox9 is a pancreatic stem cell marker. PI3K/PTEN/Akt/mTORC is an important signal for maintaining stem cells. The purpose of this study is to determine the expression pattern of Sox9 and p-Akt in human PDAC and its correlation with prognosis. Immunohistochemical analysis was used to explore the expression of Sox9 and p-Akt in 88 human PDAC patients. The Pearson's test was used to compare the clinicopathological parameters between negative and positive expressors. The Pearson's correlation analysis was used to explore the relationship between Sox9 and p-Akt expression. Kaplan-Meier's method and Cox regression analysis were used to analyze patients' survival. Theresults showed thatSox9 and p-Akt overactivated in PDAC (p=0.011, p=0.008). Sox9-positive expression issignificantly associated with distant metastasis (p=0.046). p-Akt-positive expression issignificantly associated with distant metastasis (p=0.000), TNM stage (0.001) and PCNA expression (p=0.000). Sox9 expression ispositively correlated with p-Akt expression (r=0.314, p=0.003). In 54 patients with survival information, both Sox9- and p-Akt-positive expressions areassociated with unfavorable prognosis (p=0.002, p=0.000). Sox9 and p-Akt double-positive expressor showed much poorer prognosis (p=0.000). Cox regression analysis showed thatSox9- or p-Akt-positive expression and LN metastasis were independent prognostic factors. This study provides the first evidence that Sox9 and p-Akt are both relevant to distant metastasis and proliferation. Our data suggest the potential of Sox9 and p-Akt as prognostic biomarkers for PDAC.

Modeling digits. Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.

During limb development, digits emerge from the undifferentiated mesenchymal tissue that constitutes the limb bud. It has been proposed that this process is controlled by a self-organizing Turing mechanism, whereby diffusible molecules interact to produce a periodic pattern of digital and interdigital fates. However, the identities of the molecules remain unknown. By combining experiments and modeling, we reveal evidence that a Turing network implemented by Bmp, Sox9, and Wnt drives digit specification. We develop a realistic two-dimensional simulation of digit patterning and show that this network, when modulated by morphogen gradients, recapitulates the expression patterns of Sox9 in the wild type and in perturbation experiments. Our systems biology approach reveals how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation.

New insight into reactive ductular cells of biliary atresia provided by pathological assessment of SOX9

Biliary atresia (BA) patients may survive until adolescence after effective Kasai procedure (KP). If liver fibrosis progresses even after successful KP, liver transplantation (LTx) is inevitable. Elucidation of its cause and pathophysiology would open the possibility of treating these patients by non-invasive management. SOX9 is a transcription factor that regulates bile duct development and contributes to liver regeneration and fibrosis. To elucidate the role of SOX9 in BA liver, we investigated the SOX9 expression pattern. Immunostaining with anti-SOX9 antibody was done on hepatic specimens obtained at the time of KP or LTx. We analyzed the association of SOX9 expression with clinical data. In BA livers, SOX9 was expressed in reactive ductular cells (RDCs), mostly with a nuclear-dominant pattern. SOX9 was also ectopically expressed in hepatocytes, which was more conspicuous at the timing of KP than LTx. SOX9 expression level was significantly correlated with age (days) at which KP was performed, AST and WBC count. SOX9 may contribute to RDC formation in BA patients, by affecting both RDCs and hepatocytes. SOX9 could be a key molecule to understand the mechanism of RDC formation, and this understanding would provide a therapeutic strategy for effective treatment of BA.

Expression of SOX9 in Intraductal Papillary Mucinous Neoplasms of the Pancreas

SRY (sex determining region Y) box 9 (SOX9) plays a key role in the embryologic development, differentiation, and maintenance of organs in the pancreas as well as progression of several kinds of tumors. The aim of the present study was to evaluate the expression and potential role of SOX9 in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The authors selected 27 pathological tissues from 19 IPMN cases to assess the expression of SOX9 by means of immunohistochemistry and analyzed the expression pattern of SOX9 with 78 lesions obtained from these tissues stained by SOX9. SOX9 was expressed in the normal pancreas, IPMN, and pancreatic ductal adenocarcinoma. SOX9-positive cells were confined to the lower portions of the papillary structures of IPMN. However, SOX9 was expressed in the entire epithelium once the neoplasms advanced to high-grade dysplasia and invasive carcinoma. The expression pattern of SOX9 was similar to that of CD44 in the normal pancreas and IPMN. Double staining of SOX9 and CD44 detected colocalization of SOX9 and CD44 in IPMN. Changes in the SOX9 expression pattern may be involved in the mechanisms of the malignant progression of IPMN.

Disturbed balance between SOX2 and CDX2 in human vitelline duct anomalies and intestinal duplications

Congenital gastric-type heteroplasia is common in intestinal duplications and anomalies, which originate from incomplete resorption of the omphalomesenteric duct during development. Two transcription factors determine the proximodistal specification of the gastrointestinal tract, SOX2, expressed exclusively in the proximal part of the primitive gut, and CDX2, expressed solely in the distal part. Aberrant expression of these factors may result in abnormal development and congenital abnormalities. Therefore, we analyzed the expression of SOX2 and CDX2 in a number of pediatric intestinal anomalies. We investigated the expression pattern of SOX2 and CDX2 in three congenital intestinal anomalies in which ectopic gastric tissue may be present, Meckel's diverticulum (N = 8), persistent ductus omphalomesentericus (N = 14), and intestinal duplications (N = 8). CDX2, but not SOX2, was detected in intestinal epithelial cells in tissue lacking gastric heteroplasia. In gastric-type heteroplasia, a reciprocal expression pattern existed between SOX2 and CDX2 in the gastric and intestinal tissues, respectively. Interestingly, patches of CDX2-positive cells were present within the gastric mucosa in a subset of Meckel's diverticula and intestinal duplications, suggesting that it is not the absence of CDX2, but rather the ectopic expression of SOX2 that leads to gastric tissue in the prospective intestinal tissue. This is in concordance with our previous mouse studies. Collectively, our data indicate that a fine balance between SOX2 and CDX2 expression in the gastrointestinal tract is essential for proper development and that ectopic expression of SOX2 may lead to malformations of the gut.

Sox2 marks epithelial competence to generate teeth in mammals and reptiles

Tooth renewal is initiated from epithelium associated with existing teeth. The development of new teeth requires dental epithelial cells that have competence for tooth formation, but specific marker genes for these cells have not been identified. Here, we analyzed expression patterns of the transcription factor Sox2 in two different modes of successional tooth formation: tooth replacement and serial addition of primary teeth. We observed specific Sox2 expression in the dental lamina that gives rise to successional teeth in mammals with one round of tooth replacement as well as in reptiles with continuous tooth replacement. Sox2 was also expressed in the dental lamina during serial addition of mammalian molars, and genetic lineage tracing indicated that Sox2(+) cells of the first molar give rise to the epithelial cell lineages of the second and third molars. Moreover, conditional deletion of Sox2 resulted in hyperplastic epithelium in the forming posterior molars. Our results indicate that the Sox2(+) dental epithelium has competence for successional tooth formation and that Sox2 regulates the progenitor state of dental epithelial cells. The findings imply that the function of Sox2 has been conserved during evolution and that tooth replacement and serial addition of primary teeth represent variations of the same developmental process. The expression patterns of Sox2 support the hypothesis that dormant capacity for continuous tooth renewal exists in mammals.

Expression pattern of Sox2 during mouse tooth development

The transcription factor Sox2 plays important roles in maintaining the pluripotency of embryonic stem cells and adult progenitors. However, whether Sox2 is involved in odontogenesis has not been reported. In this study, we examined the expression pattern of Sox2 during mouse incisor and molar development using real-time PCR, in situ hybridization and immunohistochemistry. Sox2 mRNA was expressed in the dental epithelium and mesenchyme while Sox2 protein was mainly detected in the epithelium from embryonic day (E) 11.5 to postnatal (PN) day 20. In the case of incisor, Sox2 mRNA and protein were expressed in most of dental epithelial cells from E11.5 to E14.5, and they were both highly expressed in the labial cervical loop area from E16.5 to PN20. During molar development, we observed an asymmetrical distribution of Sox2 protein in the epithelium from E13.5 to E16.5, with stronger signals in the lingual side. From E18.5 to PN2, Sox2 was expressed within the cervical loop area, and the stellate intermediate layer. From PN6 to PN14, Sox2 expression was confined mainly to the apical end of hertwig’s epithelium root sheath (HERS) cells. Sox2 was also detected within the perivascular region of the dental pulp at PN14 and PN20. Our results suggested that: (1) Sox2 was involved in mouse odontogenesis, and (2) it might participate in maintaining the pluripotency of the epithelial stem cells of labial cervical loop in mouse incisor development and the epithelium progenitors during molar development, (3) Sox2 might be regulated at post-transcription level during mouse odontogenesis.

Mo1977 Expression Pattern of SOX2 and CDx2 in Meckels Diverticulum

Mo1977 Expression Pattern of SOX2 and CDx2 in Meckels Diverticulum

Abstract 5083: Analysis of head and neck cancer reveals recurrent copy number aberrations and molecular subtypes exhibiting distinct expression patterns of known oncogenes in the chr3q amplicon

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease whose underlying etiology is unknown. Chung et al. (Cancer Cell 2004; 5: 489 - 500) detected HNSCC gene expression (GE) subtypes, but to our knowledge these subtypes have not been discovered in other HNSCC datasets. Moreover, we are not aware of any HNSCC studies that have examined recurrent DNA copy number (CN) aberrations in the context of GE subtypes. Numerous studies have shown that HNSCC exhibits recurrent copy number gains in chr3q26-28, a region that contains the known oncogenes SOX2, PIK3CA, and TP63. Bass et al. (Nature Genetics 2009; 41(11): 1238 - 1242) suggest that SOX2 plays a fundamental role in the development of esophageal SCC. However, it does not appear that the expression patterns of SOX2, PIK3CA, and TP63 have been investigated in HNSCC. Techniques: After receiving informed consent, we obtained tumor samples from an incident surgical series of HNSCC patients at the University of North Carolina Hospital. CN and GE assays were performed using Affymetrix Genome-Wide SNP6.0 and Agilent 44K Gene Expression platforms, respectively. GE subtypes were discovered using ConsensusClusterPlus, and their statistical significance was assessed with SigClust. DiNAMIC was used to detect recurrent CN aberrations. Results: Tumor samples from 169 patients were obtained, making this the largest genomic HNSCC series ever reported to our knowledge. After passing quality control on both platforms, GE data was available for 138 patients, while CN data was available for 110 patients; GE and CN data was available for 82 patients. Four GE subtypes were found, and all pairwise comparisons of these subtypes were statistically significant after adjusting for multiple testing. Nearest centroid methods show that our GE subtypes correspond to those of Chung et al.; three of our four GE subtypes show strong similarities to those found in lung squamous cell carcinoma. Overall, recurrent CN gains were discovered in chr3q27, chr11q13, and chr8q23; recurrent CN losses were found in chr3p21, chr9p21, and chr8p23. All of these regions harbor known oncogenes. Distinct patterns of recurrent gains and losses were noted when CN data from each GE subtype was examined, and different patterns of gain and loss were found when we examined CN data from each tumor site. Although the expression subtypes exhibit similar CN values in the chr3q26-28 amplicon, the expression patterns of SOX2, PIK3CA, and TP63 differ considerably. Conclusion: Integrated genomic analysis reveals HNSCC GE subtypes, some of which are present in lung cancer. The existence of distinct patterns of CN gain and loss in the GE subtypes suggests the presence of multiple biological pathways that play fundamental roles in the development of HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5083. doi:1538-7445.AM2012-5083

Abstract 1292: Mutually exclusive expression of SOX2 and SOX9 in lung adenocarcinoma cells and its implications

Abstract SOX family genes play critical roles in embryonic development, cell fate determination, differentiation, and proliferation. Some members of the SOX family, including SOX2 and SOX9, have been shown as hall marks of lung cancers. However, their roles in lung cancer formation or progression still need to be explored. Here we show an unique expression pattern of SOX2 and SOX9 in lung cancer cells. Using a series of previously established lung adenocarcinoma cell sub-lines which were sequentially selected for increasing cell invasiveness, we found that SOX9 was abundant in highly tumorigenic and invasive sub-lines whereas absent in less tumorigenic and low invasive ones. Interestingly, SOX2 and SOX9 were mutually exclusively expressed among those sub-lines. Forced expression and gene silencing experiments in those cell lines indicated that, while SOX9 is important for cancer cell proliferation, SOX2 is involved in regulation of cell invasion. The involvoed molecular pathways subject to regulations by SOX9 and SOX2 have been partially elucidated and will be demonstrated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1292. doi:1538-7445.AM2012-1292

Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development

Cdc42, a member of the Rho subfamily of small GTPases, is known to be a regulator of multiple cellular functions, including cytoskeletal organization, cell migration, proliferation, and apoptosis. However, its tissue-specific roles, especially in mammalian limb development, remain unclear. To investigate the physiological function of Cdc42 during limb development, we generated limb bud mesenchyme-specific inactivated Cdc42 (Cdc42fl/fl; Prx1-Cre) mice. Cdc42fl/fl; Prx1-Cre mice demonstrated short limbs and body, abnormal calcification of the cranium, cleft palate, disruption of the xiphoid process, and syndactyly. Severe defects were also found in long bone growth plate cartilage, characterized by loss of columnar organization of chondrocytes, and thickening and massive accumulation of hypertrophic chondrocytes, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed that expressions of Col10 and Mmp13 were reduced in non-resorbed hypertrophic cartilage, indicating that deletion of Cdc42 inhibited their terminal differentiation. Syndactyly in Cdc42fl/fl; Prx1-Cre mice was caused by fusion of metacarpals and a failure of interdigital programmed cell death (ID-PCD). Whole mount in situ hybridization analysis of limb buds showed that the expression patterns of Sox9 were ectopic, while those of Bmp2, Msx1, and Msx2, known to promote apoptosis in the interdigital mesenchyme, were down-regulated. These results demonstrate that Cdc42 is essential for chondrogenesis and ID-PCD during limb development.

SOX2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer

BackgroundThe transcription factor SOX2, which is involved in the induction of pluripotent stem cells and contributes to colorectal carcinogenesis, is associated with a poor prognosis in colon cancer (CC). Furthermore, SOX2 is a repressor of the transcriptional activity of β-catenin in vitro. Since the majority of CC develop via an activation of the Wnt/β-catenin signalling pathway, indicated by nuclear expression of β-catenin, we wanted to investigate the expression patterns of SOX2 and β-catenin and correlate them with the occurrence of lymph node and distant metastases as indicators of malignant progression.MethodsThe expression of SOX2 and β-catenin was investigated in a case control study utilizing a matched pair collection (N = 114) of right-sided CCs with either corresponding distant metastases (N = 57) or without distant spread (N = 57) by applying immunohistochemistry.ResultsElevated protein expression of SOX2 significantly correlated with the presence of lymph node- (p = 0.006) and distant metastases (p = 0.022). Nuclear β-catenin expression correlated significantly only with distant metastases (p = 0.001). Less than 10% of cases showed a coexpression of high levels of β-catenin and SOX2. The positivity for both markers was also associated with a very high risk for lymph-node metastases (p = 0.007) and distant spread (p = 0.028).ConclusionWe demonstrated that increased expression of either SOX2 or nuclear β-catenin are associated with distant metastases in right-sided CC. Additionally, SOX2 is also associated with lymph-node metastases. These data underline the importance of stemness-associated markers for the identification of CC with high risk for distant spread.

SOX9, through Interaction with Microphthalmia-associated Transcription Factor (MITF) and OTX2, Regulates BEST1 Expression in the Retinal Pigment Epithelium

BEST1 is highly and preferentially expressed in the retinal pigment epithelium (RPE) and causes Best macular dystrophy when mutated. We previously demonstrated that the human BEST1 upstream region -154 to +38 bp is sufficient to direct expression in the RPE of transgenic mice, and microphthalmia-associated transcription factor (MITF) and OTX2 regulate this BEST1 promoter. However, a number of questions remained. Here, we show that yeast one-hybrid screen with bait corresponding to BEST1 -120 to -88 bp identified the SOX-E factors, SOX8, SOX9, and SOX10. A paired SOX site was found in this bait, and mutation of either of the paired sites significantly decreased BEST1 promoter activity in RPE primary cultures. Among the SOX-E genes, SOX9 is highly and preferentially expressed in the RPE, and chromatin immunoprecipitation with fresh RPE cells revealed binding of SOX9, but not SOX10, to the BEST1 region where the paired SOX site is located. BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. Importantly, SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. A combination of the expression patterns of SOX9, MITF, and OTX2 yielded tissue distribution remarkably similar to that of BEST1. Lastly, the BEST1 promoter was also active in Sertoli cells of the testis in transgenic mice where SOX9 is highly expressed. These results define SOX9 as a key regulator of BEST1 expression and demonstrate for the first time its functional role in the RPE.

Molecular cloning and mRNA expression pattern of Sox9 during sex reversal in orange-spotted grouper ( Epinephelus coioides)

Sox9 is a key gene in male sex determination and gonad development. To study its potential function in the female-to-male sex reversal in orange-spotted grouper, we conducted the following studies. The Sox9 gene was cloned and full-length sequence of Sox9 mRNA was determined using the rapid amplification of cDNA ends method. The Sox9 mRNA consists of 3277 bp in size with a 328 bp 5′ untranslated region and a 1511 bp 3′ untranslated region. The 1437 bp opening reading frame encodes a 479 amino acid protein. The Sox9 gene contains 3 exons and 2 introns; the beginning and end of both introns conform to the “GT-AG” rule. RT-PCR analysis indicated that Sox9 mRNA was expressed in brain, kidney, heart, liver, muscle, stomach, intestine, spleen, testis and ovary in adult orange-spotted grouper. Artificial sex reversal was successfully performed by implanting a medicinal strip containing 17α-methyltestosterone into the groupers. By real-time PCR, we found that Sox9 was weakly expressed in the ovary-stage gonads (before treatment). Once the sex reversal began (1 week after treatment), Sox9 mRNA expression level significantly increased. However, at 2 weeks after treatment, Sox9 mRNA expression level significantly decreased to a level that was only slightly higher than that before treatment. Sox9 mRNA expression increased again at 4 weeks after treatment, and at 6 and 8 weeks, it was maintained at a high level close to that at 1 week after treatment. The results suggest that Sox9 may be one of the important factors initiating and maintaining the masculinization of orange-spotted grouper during sex reversal.

Basal cell carcinoma and pilomatrixoma mirror human follicular embryogenesis as reflected by their differential expression patterns of SOX9 and β-catenin

The current classification schemes of adnexal tumours are predominantly based on morphological and immunophenotypical similarities to adult skin structures, whereas a link between the embryology of the skin and the histogenesis of adnexal tumours has been largely neglected. To describe the expression patterns of two proteins with proven relevance for hair follicle homeostasis (SOX9 and β-catenin) during human cutaneous embryogenesis and to compare the findings with their expression in basal cell carcinoma (BCC) and pilomatrixoma. Immunohistochemical evaluation with monoclonal antibodies against SOX9 and β-catenin was carried out in embryonic and adult human scalp skin, and BCC and pilomatrixoma samples. We found that the expression patterns of SOX9 and β-catenin during human hair follicle embryogenesis mirror the patterns in BCC and pilomatrixoma in spatial distribution within the various follicular subcompartments. Beginning with the hair peg stage, nucleocytoplasmic immunoreactivity of β-catenin is exclusively confined to the emerging matrix (comparable to pilomatrixoma), whereas SOX9 is restricted to the primordial outer root sheath (comparable to BCC). An appropriate immunophenotyping validated within the conceptual framework of cutaneous developmental biology allows a logical classification of adnexal neoplasms. Expanding this approach further has the potential to revise the current classification schemes so that not only BCC and pilomatrixoma but all adnexal tumours can be categorized logically.

Sox9, more than a marker of the outer root sheath: spatiotemporal expression pattern during human cutaneous embryogenesis

The sex-determining gene Sox9 was recently unexpectedly found to have an essential role in outer root sheath differentiation. It was also characterized as a general marker of basal cell carcinoma. Herein, we describe its spatiotemporal expression pattern outside the hair follicle during human cutaneous embryogenesis. We examined immunohistochemically samples from embryonic and fetal human skin for the expression of SOX9 using standard techniques. For comparison reasons, we also included scalp skin from adults. SOX9 is expressed in the developing nail organ, eccrine glands, blood vessels and melanocytes/melanoblasts. In the nail organ, the nail bed but not the nail matrix was immunoreactive for SOX9. In plantar skin, SOX9 specifically labels the evolving eccrine glands but not the interfollicular keratinocytes. The distinctive expression pattern of SOX9 during human cutaneous embryogenesis indicates a key role in skin homeostasis that includes but goes beyond its role in outer root sheath differentiation. Studying immunohistochemical markers in developing human skin has the potential to further our understanding of adult skin physiology and to deepen our concepts especially of the histogenesis of adnexal tumors (including those of the nail unit) and the relationship of the various adnexal structures to each other.

Loss of ATRX in Chondrocytes Has Minimal Effects on Skeletal Development

BackgroundMutations in the human ATRX gene cause developmental defects, including skeletal deformities and dwarfism. ATRX encodes a chromatin remodeling protein, however the role of ATRX in skeletal development is currently unknown.Methodology/Principal FindingsWe induced Atrx deletion in mouse cartilage using the Cre-loxP system, with Cre expression driven by the collagen II (Col2a1) promoter. Growth rate, body size and weight, and long bone length did not differ in AtrxCol2cre mice compared to control littermates. Histological analyses of the growth plate did not reveal any differences between control and mutant mice. Expression patterns of Sox9, a transcription factor required for cartilage morphogenesis, and p57, a marker of cell cycle arrest and hypertrophic chondrocyte differentiation, was unaffected. However, loss of ATRX in cartilage led to a delay in the ossification of the hips in some mice. We also observed hindlimb polydactily in one out of 61 mutants.Conclusions/SignificanceThese findings indicate that ATRX is not directly required for development or growth of cartilage in the mouse, suggesting that the short stature in ATR-X patients is caused by defects in cartilage-extrinsic mechanisms.

Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development

The development of the inner ear involves complex processes of morphological changes, patterning and cell fate specification that are under strict molecular control. SOX2 and SOX9 are SOX family transcription factors that are involved in the regulation of one or more of these processes. Previous findings have shown early expression of SOX9 in the otic placode and vesicle at E8.5–E9.5. Here we describe in detail, the expression pattern of SOX9 in the developing mouse inner ear beyond the otocyst stage and compare it with that of SOX2 from E9.5 to E18.5 using double fluorescence immunohistochemistry. We found that SOX9 was widely expressed in the otic epithelium, periotic mesenchyme and cartilaginous otic capsule. SOX2 persistently marked the prosensory and sensory epithelia. During the development of the sensory epithelia, SOX2 was initially expressed in all prosensory regions and later in both the supporting and hair cells up to E15.5, when its expression in hair cells gradually diminished. SOX9 expression overlapped with that of SOX2 in the prosensory and sensory region until E14.5 when its expression was restricted to supporting cells. This initial overlap but subsequent differential expression of SOX2 and SOX9 in the sensory epithelia, suggest that SOX2 and SOX9 may have distinct roles in molecular pathways that direct cells towards different cell fates.