Journal articles: 'Sox9b'

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Raghuveer, Kavarthapu, and Balasubramanian Senthilkumaran. "Isolation of sox9 duplicates in catfish: localization, differential expression pattern during gonadal development and recrudescence, and hCG-induced up-regulation of sox9 in testicular slices." REPRODUCTION 140, no. 3 (September 2010): 477–87. http://dx.doi.org/10.1530/rep-10-0200.

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In vertebrates, sox9 is a transcription factor that plays a crucial role in testicular development and chondrogenesis. Here, we report cloning of isoforms of sox9 (sox9a and sox9b) from air-breathing catfish Clarias gariepinus, which undergoes an annual reproductive cycle. Tissue distribution pattern showed differential expression of sox9 duplicates, wherein both forms were highly expressed in brain and gonads. Furthermore, we observed a dimorphic expression pattern of sox9a and sox9b in both adult and developing gonads using RT-PCR, indicating that sox9a retained its function in testis while sox9b might have a new role to play in ovary. Changes in sox9 mRNA levels using real-time quantitative PCR (qRT-PCR) during the seasonal reproductive cycle revealed that sox9a transcript in testis was abundant during testicular recrudescence (during spermatogenesis), and its expression significantly decreased during spawning and post-spawning phases. Furthermore, treatments of human chorionic gonadotropin and 11-ketotestosterone in vitro up-regulated sox9a mRNA levels in the testicular slices at 12 and 24 h time points, suggesting that gonadotropins might stimulate sox9 expression. These results suggest that sox9 might have a plausible role in the entrainment of the testicular cycle. In contrast, during the ovarian cycle, sox9b mRNA levels gradually declined from preparatory to post-spawning phases. Immunohistochemical (IHC) data showed that, in testis, sox9 is detectable in Sertoli and spermatogonial cell types except spermatid/spermatozoa. In the ovary, it is localized in the ooplasm of primary and pre-vitellogenic oocytes. These results were further confirmed by whole-mount IHC and qRT-PCR.

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Steeman, Tomás J., Juan A. Rubiolo, Laura E. Sánchez, Nora B. Calcaterra, and Andrea M. J. Weiner. "Conservation of Zebrafish MicroRNA-145 and Its Role during Neural Crest Cell Development." Genes 12, no. 7 (June 30, 2021): 1023. http://dx.doi.org/10.3390/genes12071023.

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The neural crest is a multipotent cell population that develops from the dorsal neural fold of vertebrate embryos in order to migrate extensively and differentiate into a variety of tissues. A number of gene regulatory networks coordinating neural crest cell specification and differentiation have been extensively studied to date. Although several publications suggest a common role for microRNA-145 (miR-145) in molecular reprogramming for cell cycle regulation and/or cellular differentiation, little is known about its role during in vivo cranial neural crest development. By modifying miR-145 levels in zebrafish embryos, abnormal craniofacial development and aberrant pigmentation phenotypes were detected. By whole-mount in situ hybridization, changes in expression patterns of col2a1a and Sry-related HMG box (Sox) transcription factors sox9a and sox9b were observed in overexpressed miR-145 embryos. In agreement, zebrafish sox9b expression was downregulated by miR-145 overexpression. In silico and in vivo analysis of the sox9b 3′UTR revealed a conserved potential miR-145 binding site likely involved in its post-transcriptional regulation. Based on these findings, we speculate that miR-145 participates in the gene regulatory network governing zebrafish chondrocyte differentiation by controlling sox9b expression.

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Russell, Jacquelyn O., Sungjin Ko, Satdarshan P. Monga, and Donghun Shin. "Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish." Stem Cells International 2019 (March 12, 2019): 1–11. http://dx.doi.org/10.1155/2019/8451282.

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Liver regeneration after most forms of injury is mediated through the proliferation of hepatocytes. However, when hepatocyte proliferation is impaired, such as during chronic liver disease, liver progenitor cells (LPCs) arising from the biliary epithelial cell (BEC) compartment can give rise to hepatocytes to mediate hepatic repair. Promotion of LPC-to-hepatocyte differentiation in patients with chronic liver disease could serve as a potentially new therapeutic option, but first requires the identification of the molecular mechanisms driving this process. Notch signaling has been identified as an important signaling pathway promoting the BEC fate during development and has also been implicated in regulating LPC differentiation during regeneration. SRY-related HMG box transcription factor 9 (Sox9) is a direct target of Notch signaling in the liver, and Sox9 has also been shown to promote the BEC fate during development. We have recently shown in a zebrafish model of LPC-driven liver regeneration that inhibition of Hdac1 activity through MS-275 treatment enhances sox9b expression in LPCs and impairs LPC-to-hepatocyte differentiation. Therefore, we hypothesized that inhibition of Notch signaling would promote LPC-to-hepatocyte differentiation by repressing sox9b expression in zebrafish. We ablated the hepatocytes of Tg(fabp10a:CFP-NTR) larvae and blocked Notch activation during liver regeneration through treatment with γ-secretase inhibitor LY411575 and demonstrated enhanced induction of Hnf4a in LPCs. Alternatively, enhancing Notch signaling via Notch3 intracellular domain (N3ICD) overexpression impaired Hnf4a induction. Hepatocyte ablation in sox9b heterozygous mutant embryos enhanced Hnf4a induction, while BEC-specific Sox9b overexpression impaired LPC-to-hepatocyte differentiation. Our results establish the Notch-Sox9b signaling axis as inhibitory to LPC-to-hepatocyte differentiation in a well-established in vivo LPC-driven liver regeneration model.

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Burns, Felipe R., Kevin A. Lanham, Kong M. Xiong, Alex J. Gooding, Richard E. Peterson, and Warren Heideman. "Analysis of the zebrafish sox9b promoter: Identification of elements that recapitulate organ-specific expression of sox9b." Gene 578, no. 2 (March 2016): 281–89. http://dx.doi.org/10.1016/j.gene.2015.12.041.

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Gao, Ce, Weidong Huang, Yuqi Gao, Li Jan Lo, Lingfei Luo, Honghui Huang, Jun Chen, and Jinrong Peng. "Zebrafish hhex-null mutant develops an intrahepatic intestinal tube due to de-repression of cdx1b and pdx1." Journal of Molecular Cell Biology 11, no. 6 (November 14, 2018): 448–62. http://dx.doi.org/10.1093/jmcb/mjy068.

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Abstract The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder, and pancreatic duct. Haematopoietically expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD; however, the molecular mechanism remains elusive. Here, we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The hepatobiliary duct part of the mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty acid-binding protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 are expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 could restore the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis showed that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b, Pdx1, and Sox9b form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.

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Li, Ming, Chengtian Zhao, Ying Wang, Zhixing Zhao, and Anming Meng. "Zebrafish sox9b is an early neural crest marker." Development Genes and Evolution 212, no. 4 (April 18, 2002): 203–6. http://dx.doi.org/10.1007/s00427-002-0235-2.

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Guo, Huiping, Xinlu Du, Ying Zhang, Jiacheng Wu, Chenghui Wang, Mingyou Li, Xianxin Hua, Xin A. Zhang, and Jizhou Yan. "Specific miRNA-G Protein-Coupled Receptor Networks Regulate Sox9a/Sox9b Activities to Promote Gonadal Rejuvenation in Zebrafish." STEM CELLS 37, no. 9 (July 8, 2019): 1189–99. http://dx.doi.org/10.1002/stem.3040.

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Plavicki, Jessica S., Tracie R. Baker, Felipe R. Burns, Kong M. Xiong, Alex J. Gooding, Peter Hofsteen, Richard E. Peterson, and Warren Heideman. "Construction and characterization of a sox9b transgenic reporter line." International Journal of Developmental Biology 58, no. 9 (2014): 693–99. http://dx.doi.org/10.1387/ijdb.140288jp.

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9

Rodríguez-Marí, Adriana, Yi-Lin Yan, Ruth A. BreMiller, Catherine Wilson, Cristian Cañestro, and John H. Postlethwait. "Characterization and expression pattern of zebrafish anti-Müllerian hormone (amh) relative to sox9a, sox9b, and cyp19a1a, during gonad development." Gene Expression Patterns 5, no. 5 (June 2005): 655–67. http://dx.doi.org/10.1016/j.modgep.2005.02.008.

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Delous, Marion, Chunyue Yin, Donghun Shin, Nikolay Ninov, Juliana Debrito Carten, Luyuan Pan, Taylur P. Ma, Steven A. Farber, Cecilia B. Moens, and Didier Y. R. Stainier. "sox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development." PLoS Genetics 8, no. 6 (June 14, 2012): e1002754. http://dx.doi.org/10.1371/journal.pgen.1002754.

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11

Liu, Jifang, Shaojun Liu, Min Tao, Wei Li, and Yun Liu. "Isolation and Expression Analysis of Testicular Type Sox9b in Allotetraploid Fish." Marine Biotechnology 9, no. 3 (January 23, 2007): 329–34. http://dx.doi.org/10.1007/s10126-006-6123-4.

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12

Yoshioka, Wataru, and Chiharu Tohyama. "Mechanisms of Developmental Toxicity of Dioxins and Related Compounds." International Journal of Molecular Sciences 20, no. 3 (January 31, 2019): 617. http://dx.doi.org/10.3390/ijms20030617.

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Dioxins and related compounds induce morphological abnormalities in developing animals in an aryl hydrocarbon receptor (AhR)-dependent manner. Here we review the studies in which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is used as a prototypical compound to elucidate the pathogenesis of morphological abnormalities. TCDD-induced cleft palate in fetal mice involves a delay in palatogenesis and dissociation of fused palate shelves. TCDD-induced hydronephrosis, once considered to be caused by the anatomical obstruction of the ureter, is now separated into TCDD-induced obstructive and non-obstructive hydronephrosis, which develops during fetal and neonatal periods, respectively. In the latter, a prostaglandin E2 synthesis pathway and urine concentration system are involved. TCDD-induced abnormal development of prostate involves agenesis of the ventral lobe. A suggested mechanism is that AhR activation in the urogenital sinus mesenchyme by TCDD modulates the wingless-type MMTV integration site family (WNT)/β-catenin signaling cascade to interfere with budding from urogenital sinus epithelium. TCDD exposure to zebrafish embryos induces loss of epicardium progenitor cells and heart malformation. AHR2-dependent downregulation of Sox9b expression in cardiomyocytes is a suggested underlying mechanism. TCDD-induced craniofacial malformation in zebrafish is considered to result from the AHR2-dependent reduction in SRY-box 9b (SOX9b), probably partly via the noncoding RNA slincR, resulting in the underdevelopment of chondrocytes and cartilage.

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Tsunogai, Yuri, Motohiro Miyadai, Yusuke Nagao, Keisuke Sugiwaka, Robert N. Kelsh, Masahiko Hibi, and Hisashi Hashimoto. "Contribution of sox9b to pigment cell formation in medaka fish." Development, Growth & Differentiation 63, no. 9 (December 2021): 516–22. http://dx.doi.org/10.1111/dgd.12760.

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Huang, Wei, Rebecca L. Beer, Fabien Delaspre, Guangliang Wang, Hannah E. Edelman, Hyewon Park, Mizuki Azuma, and Michael J. Parsons. "Sox9b is a mediator of retinoic acid signaling restricting endocrine progenitor differentiation." Developmental Biology 418, no. 1 (October 2016): 28–39. http://dx.doi.org/10.1016/j.ydbio.2016.08.019.

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Manfroid, Isabelle, Aurélie Ghaye, François Naye, Nathalie Detry, Sarah Palm, Luyuan Pan, Taylur P. Ma, et al. "Zebrafish sox9b is crucial for hepatopancreatic duct development and pancreatic endocrine cell regeneration." Developmental Biology 366, no. 2 (June 2012): 268–78. http://dx.doi.org/10.1016/j.ydbio.2012.04.002.

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16

Ko, Sungjin, Jacquelyn O. Russell, Jianmin Tian, Ce Gao, Makoto Kobayashi, Rilu Feng, Xiaodong Yuan, et al. "Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8." Gastroenterology 156, no. 1 (January 2019): 187–202. http://dx.doi.org/10.1053/j.gastro.2018.09.039.

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17

Xiong, Kong M., Richard E. Peterson, and Warren Heideman. "Aryl Hydrocarbon Receptor-Mediated Down-Regulation of Sox9b Causes Jaw Malformation in Zebrafish Embryos." Molecular Pharmacology 74, no. 6 (September 10, 2008): 1544–53. http://dx.doi.org/10.1124/mol.108.050435.

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King, Alex C., Michelle Gut, and Armin K. Zenker. "Shedding new light on early sex determination in zebrafish." Archives of Toxicology 94, no. 12 (September 25, 2020): 4143–58. http://dx.doi.org/10.1007/s00204-020-02915-y.

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Abstract In contrast to established zebrafish gene annotations, the question of sex determination has still not been conclusively clarified for developing zebrafish, Danio rerio, larvae, 28 dpf or earlier. Recent studies indicate polygenic sex determination (PSD), with the genes being distributed throughout the genome. Early genetic markers of sex in zebrafish help unravel co-founding sex-related differences to apply to human health and environmental toxicity studies. A qPCR-based method was developed for six genes: cytochrome P450, family 17, subfamily A, polypeptide 1 (cyp17a1); cytochrome P450, family 19, subfamily A, polypeptide 1a (cyp19a1a); cytochrome P450, family 19, subfamily A, polypeptides 1b (cyp19a1b); vitellogenin 1 (vtg1); nuclear receptor subfamily 0, group B, member 1 (nr0b1), sry (sex-determining region Y)-box 9b (sox9b) and actin, beta 1 (actb1), the reference gene. Sry-box 9a (Sox9a), insulin-like growth factor 3 (igf3) and double sex and mab-3 related transcription factor 1 (dmrt1), which are also known to be associated with sex determination, were used in gene expression tests. Additionally, Next-Generation-Sequencing (NGS) sequenced the genome of two adult female and male and two juveniles. PCR analysis of adult zebrafish revealed sex-specific expression of cyp17a1, cyp19a1a, vtg1, igf3 and dmrt1, the first four strongly expressed in female zebrafish and the last one highly expressed in male conspecifics. From NGS, nine female and four male-fated genes were selected as novel for assessing zebrafish sex, 28 dpf. Differences in transcriptomes allowed allocation of sex-specific genes also expressed in juvenile zebrafish.

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Garcia, Gloria R., Britton C. Goodale, Michelle W. Wiley, Jane K. La Du, David A. Hendrix, and Robert L. Tanguay. "In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression." Molecular Pharmacology 91, no. 6 (April 6, 2017): 609–19. http://dx.doi.org/10.1124/mol.117.108233.

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Han, Jiangyuan, Yan Hu, Yongmei Qi, Cong Yuan, Sajid Naeem, and Dejun Huang. "High temperature induced masculinization of zebrafish by down-regulation of sox9b and esr1 via DNA methylation." Journal of Environmental Sciences 107 (September 2021): 160–70. http://dx.doi.org/10.1016/j.jes.2021.01.032.

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Shen, Xue-Yan, Jian-Zhou Cui, Qing-Li Gong, and Yoshitaka Nagahama. "Cloning of the full-length coding sequence and expression analysis of Sox9b in guppy (Poecilia reticulata)." Fish Physiology and Biochemistry 33, no. 3 (March 9, 2007): 195–202. http://dx.doi.org/10.1007/s10695-007-9131-z.

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Wei, Ling, Xiaoyan Li, Minghui Li, Yaohao Tang, Jing Wei, and Deshou Wang. "Dmrt1 directly regulates the transcription of the testis-biased Sox9b gene in Nile tilapia (Oreochromis niloticus)." Gene 687 (March 2019): 109–15. http://dx.doi.org/10.1016/j.gene.2018.11.016.

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Hofsteen, Peter, Jessica Plavicki, Shaina D. Johnson, Richard E. Peterson, and Warren Heideman. "Sox9b Is Required for Epicardium Formation and Plays a Role in TCDD-Induced Heart Malformation in Zebrafish." Molecular Pharmacology 84, no. 3 (June 17, 2013): 353–60. http://dx.doi.org/10.1124/mol.113.086413.

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Dalcq, Julia, Vincent Pasque, Aurélie Ghaye, Arnaud Larbuisson, Patrick Motte, Joseph A. Martial, and Marc Muller. "RUNX3, EGR1 and SOX9B Form a Regulatory Cascade Required to Modulate BMP-Signaling during Cranial Cartilage Development in Zebrafish." PLoS ONE 7, no. 11 (November 27, 2012): e50140. http://dx.doi.org/10.1371/journal.pone.0050140.

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Chen, Tianyi, Haoze Chen, Anli Wang, Weixuan Yao, Zhongshi Xu, Binjie Wang, Jiye Wang, and Yuanzhao Wu. "Methyl Parathion Exposure Induces Development Toxicity and Cardiotoxicity in Zebrafish Embryos." Toxics 11, no. 1 (January 15, 2023): 84. http://dx.doi.org/10.3390/toxics11010084.

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Methyl parathion (MP) has been widely used as an organophosphorus pesticide for food preservation and pest management, resulting in its accumulation in the aquatic environment. However, the early developmental toxicity of MP to non-target species, especially aquatic vertebrates, has not been thoroughly investigated. In this study, zebrafish embryos were treated with 2.5, 5, or 10 mg/L of MP solution until 72 h post-fertilization (hpf). The results showed that MP exposure reduced spontaneous movement, hatching, and survival rates of zebrafish embryos and induced developmental abnormalities such as shortened body length, yolk edema, and spinal curvature. Notably, MP was found to induce cardiac abnormalities, including pericardial edema and decreased heart rate. Exposure to MP resulted in the accumulation of reactive oxygen species (ROS), decreased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, elevated malondialdehyde (MDA) levels, and caused cardiac apoptosis in zebrafish embryos. Moreover, MP affected the transcription of cardiac development-related genes (vmhc, sox9b, nppa, tnnt2, bmp2b, bmp4) and apoptosis-related genes (p53, bax, bcl2). Astaxanthin could rescue MP-induced heart development defects by down-regulating oxidative stress. These findings suggest that MP induces cardiac developmental toxicity and provides additional evidence of MP toxicity to aquatic organisms.

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Yan, Rui, Jie Ding, Yuanjie Wei, Qianlei Yang, Xiaoyun Zhang, Hairu Huang, Zhuoyue Shi, et al. "Melatonin Prevents NaAsO2-Induced Developmental Cardiotoxicity in Zebrafish through Regulating Oxidative Stress and Apoptosis." Antioxidants 11, no. 7 (June 29, 2022): 1301. http://dx.doi.org/10.3390/antiox11071301.

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Melatonin is an indoleamine hormone secreted by the pineal gland. It has antioxidation and anti-apoptosis effects and a clear protective effect against cardiovascular diseases. Our previous studies demonstrated that embryonic exposure to sodium arsenite (NaAsO2) can lead to an abnormal cardiac development. The aim of this study was to determine whether melatonin could protect against NaAsO2-induced generation of reactive oxygen species (ROS), oxidative stress, apoptosis, and abnormal cardiac development in a zebrafish (Danio rerio) model. We found that melatonin decreased NaAsO2-induced zebrafish embryonic heart malformations and abnormal heart rates at a melatonin concentration as low as 10−9 mol/L. The NaAsO2-induced oxidative stress was counteracted by melatonin supplementation. Melatonin blunted the NaAsO2-induced overproduction of ROS, the upregulation of oxidative stress-related genes (sod2, cat, gpx, nrf2, ho-1), and the production of antioxidant enzymes (Total SOD, SOD1, SOD2, CAT). Melatonin attenuated the NaAsO2-induced oxidative damage, DNA damage, and apoptosis, based on malonaldehyde and 8-OHdG levels and apoptosis-related gene expression (caspase-3, bax, bcl-2), respectively. Melatonin also maintained the control levels of heart development-related genes (nkx2.5, sox9b) affected by NaAsO2. In conclusion, melatonin protected against NaAsO2-induced heart malformations by inhibiting the oxidative stress and apoptosis in zebrafish.

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Kan, Yuting, Ying Zhong, Muhammad Jawad, Xiao Chen, Dong Liu, Mingchun Ren, Gangchun Xu, Lang Gui, and Mingyou Li. "Establishment of a Coilia nasus Gonadal Somatic Cell Line Capable of Sperm Induction In Vitro." Biology 11, no. 7 (July 13, 2022): 1049. http://dx.doi.org/10.3390/biology11071049.

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Coilia nasus is an important economic anadromous migratory fish of the Yangtze River in China. In recent years, overfishing and the deterioration of the ecological environment almost led to the extinction of the wild resources of C.nasus. Thus, there is an urgent need to protect this endangered fish. Recently, cell lines derived from fish have proven a promising tool for studying important aspects of aquaculture. In this study, a stable C. nasus gonadal somatic cell line (CnCSC) was established and characterized. After over one year of cell culture (>80 passages), this cell line kept stable growth. RT-PCR results revealed that the CnGSC expressed some somatic cell markers such as clu, fshr, hsd3β, and sox9b instead of germ cell markers like dazl, piwi, and vasa. The strong phagocytic activity of CnGSC suggested that it contained a large number of Sertoli cells. Interestingly, CnGSC could induce medaka spermatogonial cells (SG3) to differentiate into elongated spermatids while co-cultured together. In conclusion, we established a C. nasus gonadal somatic cell line capable of sperm induction in vitro. This research provides scientific evidence for the long-term culture of a gonadal cell line from farmed fish, which would lay the foundation for exploring the regulatory mechanisms between germ cells and somatic cells in fish.

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Cheng, Peng, Zhangfan Chen, Wenteng Xu, Na Wang, Qian Yang, Rui Shi, Xihong Li, Zhongkai Cui, Jiayu Cheng, and Songlin Chen. "Potential Involvement of ewsr1-w Gene in Ovarian Development of Chinese Tongue Sole, Cynoglossus semilaevis." Animals 12, no. 19 (September 20, 2022): 2503. http://dx.doi.org/10.3390/ani12192503.

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Ewsr1 encodes a protein that acts as a multifunctional molecule in a variety of cellular processes. The full-length of Cs-ewsr1-w and Cs-ewsr1-z were cloned in Chinese tongue sole (Cynoglossus semilaevis). The open reading frame (ORF) of Cs-ewsr1-w was 1,767 bp that encoded 589 amino acids, while Cs-ewsr1-z was 1,794 bp that encoded 598 amino acids. Real-time PCR assays showed that Cs-ewsr1-w exhibited significant female-biased expression and could be hardly detected in male. It has the most abundant expression in ovaries among eight healthy tissues. Its expression in ovary increased gradually from 90 d to 3 y with C. semilaevis ovarian development and reached the peak at 3 y. After Cs-ewsr1-w knockdown with siRNA interference, several genes related to gonadal development including foxl2, sox9b and pou5f1 were down-regulated in ovarian cell line, suggesting the possible participation of Cs-ewsr1-w in C. semilaevis ovarian development. The dual-luciferase reporter assay revealed that the -733/-154 bp Cs-ewsr1-w promoter fragment exhibited strong transcription activity human embryonic kidney (HEK) 293T cell line. The mutation of a MAF BZIP Transcription Factor K (Mafk) binding site located in this fragment suggested that transcription factor Mafk might play an important role in Cs-ewsr1-w basal transcription. Our results will provide clues on the gene expression level, transcriptional regulation and knock-down effect of ewsr1 gene during ovarian development in teleost.

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Nakamura, Shuhei, Yumiko Aoki, Daisuke Saito, Yoko Kuroki, Asao Fujiyama, Kiyoshi Naruse, and Minoru Tanaka. "Sox9b/sox9a2-EGFP transgenic medaka reveals the morphological reorganization of the gonads and a common precursor of both the female and male supporting cells." Molecular Reproduction and Development 75, no. 3 (2007): 472–76. http://dx.doi.org/10.1002/mrd.20764.

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Yan, Yi-Lin, Craig T. Miller, Robert Nissen, Amy Singer, Dong Liu, Anette Kirn, Bruce Draper, et al. "A zebrafish sox9 gene required for cartilage morphogenesis." Development 129, no. 21 (November 1, 2002): 5065–79. http://dx.doi.org/10.1242/dev.129.21.5065.

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The molecular genetic mechanisms of cartilage construction are incompletely understood. Zebrafish embryos homozygous for jellyfish (jef)mutations show craniofacial defects and lack cartilage elements of the neurocranium, pharyngeal arches, and pectoral girdle similar to humans with campomelic dysplasia. We show that two alleles of jef contain mutations in sox9a, one of two zebrafish orthologs of the human transcription factor SOX9. A mutation induced by ethyl nitrosourea changed a conserved nucleotide at a splice junction and severely reduced splicing of sox9a transcript. A retrovirus insertion intosox9a disrupted its DNA-binding domain. Inhibiting splicing of thesox9a transcript in wild-type embryos with splice site-directed morpholino antisense oligonucleotides produced a phenotype like jefmutant larvae, and caused sox9a transcript to accumulate in the nucleus; this accumulation can serve as an assay for the efficacy of a morpholino independent of phenotype. RNase-protection assays showed that in morpholino-injected animals, the percent of splicing inhibition decreased from 80% at 28 hours post fertilization to 45% by 4 days. Homozygous mutant embryos had greatly reduced quantities of col2a1 message, the major collagen of cartilage. Analysis of dlx2 expression showed that neural crest specification and migration was normal in jef (sox9a)embryos. Confocal images of living embryos stained with BODIPY-ceramide revealed at single-cell resolution the formation of precartilage condensations in mutant embryos. Besides the lack of overt cartilage differentiation,pharyngeal arch condensations in jef (sox9a) mutants lacked three specific morphogenetic behaviors: the stacking of chondrocytes into orderly arrays, the individuation of pharyngeal cartilage organs and the proper shaping of individual cartilages. Despite the severe reduction of cartilages, analysis of titin expression showed normal muscle patterning in jef (sox9a) mutants. Likewise, calcein labeling revealed that early bone formation was largely unaffected injef (sox9a) mutants. These studies show that jef(sox9a) is essential for both morphogenesis of condensations and overt cartilage differentiation.

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Turcatel, Gianluca, Katelyn Millette, Matthew Thornton, Stephanie Leguizamon, Brendan Grubbs, Wei Shi, and David Warburton. "Cartilage rings contribute to the proper embryonic tracheal epithelial differentiation, metabolism, and expression of inflammatory genes." American Journal of Physiology-Lung Cellular and Molecular Physiology 312, no. 2 (February 1, 2017): L196—L207. http://dx.doi.org/10.1152/ajplung.00127.2016.

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The signaling cross talk between the tracheal mesenchyme and epithelium has not been researched extensively, leaving a substantial gap of knowledge in the mechanisms dictating embryonic development of the proximal airways by the adjacent mesenchyme. Recently, we reported that embryos lacking mesenchymal expression of Sox9 did not develop tracheal cartilage rings and showed aberrant differentiation of the tracheal epithelium. Here, we propose that tracheal cartilage provides local inductive signals responsible for the proper differentiation, metabolism, and inflammatory status regulation of the tracheal epithelium. The tracheal epithelium of mesenchyme-specific Sox9Δ/Δmutant embryos showed altered mRNA expression of various epithelial markers such as Pb1fa1, surfactant protein B ( Sftpb), secretoglobulin, family 1A, member 1 ( Scgb1a1), and trefoil factor 1 ( Tff1). In vitro tracheal epithelial cell cultures confirmed that tracheal chondrocytes secrete factors that inhibit club cell differentiation. Whole gene expression profiling and ingenuity pathway analysis showed that the tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β) signaling pathways were significantly altered in the Sox9 mutant trachea. TNF-α and IFN-γ interfered with the differentiation of tracheal epithelial progenitor cells into mature epithelial cell types in vitro. Mesenchymal knockout of Tgf-β1 in vivo resulted in altered differentiation of the tracheal epithelium. Finally, mitochondrial enzymes involved in fat and glycogen metabolism, cytochrome c oxidase subunit VIIIb ( Cox8b) and cytochrome c oxidase subunit VIIa polypeptide 1 ( Cox7a1), were strongly upregulated in the Sox9 mutant trachea, resulting in increases in the number and size of glycogen storage vacuoles. Our results support a role for tracheal cartilage in modulation of the differentiation and metabolism and the expression of inflammatory-related genes in the tracheal epithelium by feeding into the TNF-α, IFN-γ, and TGF-β signaling pathways.

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Formeister, Eric J., Ayn L. Sionas, David K. Lorance, Carey L. Barkley, Ginny H. Lee, and Scott T. Magness. "Distinct SOX9 levels differentially mark stem/progenitor populations and enteroendocrine cells of the small intestine epithelium." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 5 (May 2009): G1108—G1118. http://dx.doi.org/10.1152/ajpgi.00004.2009.

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SOX transcription factors have the capacity to modulate stem/progenitor cell proliferation and differentiation in a dose-dependent manner. SOX9 is expressed in the small intestine epithelial stem cell zone. Therefore, we hypothesized that differential levels of SOX9 may exist, influencing proliferation and/or differentiation of the small intestine epithelium. Sox9 expression levels in the small intestine were investigated using a Sox9 enhanced green fluorescent protein ( Sox9 EGFP) transgenic mouse. Sox9 EGFP levels correlate with endogenous SOX9 levels, which are expressed at two steady-state levels, termed Sox9 EGFPLO and Sox9 EGFPHI. Crypt-based columnar cells are Sox9 EGFPLO and demonstrate enriched expression of the stem cell marker, Lgr5. Sox9 EGFPHI cells express chromogranin A and substance P but do not express Ki67 and neurogenin3, indicating that Sox9 EGFPHI cells are postmitotic enteroendocrine cells. Overexpression of SOX9 in a crypt cell line stopped proliferation and induced morphological changes. These data support a bimodal role for SOX9 in the intestinal epithelium, where low SOX9 expression supports proliferative capacity, and high SOX9 expression suppresses proliferation.

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Shi, Zhongcheng, Chi-I. Chiang, Toni-Ann Mistretta, Angela Major, and Yuko Mori-Akiyama. "SOX9 directly regulates IGFBP-4 in the intestinal epithelium." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 1 (July 1, 2013): G74—G83. http://dx.doi.org/10.1152/ajpgi.00086.2013.

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SOX9 regulates cell lineage specification by directly regulating target genes in a discrete number of tissues, and previous reports have shown cell proliferative and suppressive roles for SOX9. Although SOX9 is expressed in colorectal cancer, only a few direct targets have been identified in intestinal epithelial cells. We previously demonstrated increased proliferation in Sox9-deficient crypts through loss-of-function studies, indicating that SOX9 suppresses cell proliferation. In this study, crypt epithelial cells isolated from Sox9-deficient mice were used to identify potential target genes of SOX9. Insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4), an inhibitor of the IGF/IGF receptor pathway, was significantly downregulated in Sox9-deficient intestinal epithelial cells and adenoma cells of Sox9-deficient Apc Min/+ mice. Immunolocalization experiments revealed that IGFBP-4 colocalized with SOX9 in mouse and human intestinal epithelial cells and in specimens from patients with primary colorectal cancer. Reporter assays and chromatin immunoprecipitation demonstrated direct binding of SOX9 to the IGFBP-4 promoter. Overexpression of SOX9 attenuated cell proliferation, which was restored following treatment with a neutralizing antibody against IGFBP-4. These results suggest that SOX9 regulates cell proliferation, at least in part via IGFBP-4. Furthermore, the antiproliferative effect of SOX9 was confirmed in vivo using Sox9-deficient mice, which showed increased tumor burden when bred with Apc Min/+ mice. Our results demonstrate, for the first time, that SOX9 is a transcriptional regulator of IGFBP-4 and that SOX9-induced activation of IGFBP-4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer.

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Kim, So-Sun, David Nahm-Joon Kim, Chang-Ju Lee, Hae-Kyun Yoo, Soon-Gyu Byun, Hyun-Jeong Lim, Jin Choi, and Jang-Su Park. "The Potential Sex Determination Genes, Sox9a and Cyp19a, in Walleye Pollock (Gadus Chalcogrammus) Are Influenced by Water Temperature." Journal of Marine Science and Engineering 8, no. 7 (July 8, 2020): 501. http://dx.doi.org/10.3390/jmse8070501.

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Our aim was to study the relationship between the sex-determining genes, sox9a and cyp19a, and water temperature in Gadus chalcogrammus. We assessed the sex ratio based on the expression levels of sox9a and cyp19a at different water temperatures (5, 8, 11, and 14 °C) and at different stages of walleye pollock development (embryos, larvae, and juveniles). Next, we used immature walleye pollock to assess sox9a expression in males and cyp19a and vitellogenin (VTG) expression in females at different water temperatures. Males expressed sox9a in the gonadal tissues, while females expressed cyp19a in the gonadal tissues and VTG in the blood plasma. In the first experiment, cyp19a expression was higher at 5 °C and 8 °C, and sox9a expression was higher at 11 and 14 °C. In the second experiment, sox9a expression remained relatively stable, but cyp19a expression decreased with increasing temperature, decreasing significantly after 14 °C. Similar patterns were also observed for VTG expression. These results indicate that lower water temperatures increase cyp19a expression, which increases the female ratio. Higher water temperatures increase sox9a expression, which increases the male ratio. Therefore, this study highlights the potential of the sex-determining genes and the influence of water temperature.

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Van Landeghem, Laurianne, M. Agostina Santoro, Adrienne E. Krebs, Amanda T. Mah, Jeffrey J. Dehmer, Adam D. Gracz, Brooks P. Scull, Kirk McNaughton, Scott T. Magness, and P. Kay Lund. "Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation." American Journal of Physiology-Gastrointestinal and Liver Physiology 302, no. 10 (May 15, 2012): G1111—G1132. http://dx.doi.org/10.1152/ajpgi.00519.2011.

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Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration.

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Huang, Wendong, Xin Zhou, Véronique Lefebvre, and Benoit de Crombrugghe. "Phosphorylation of SOX9 by Cyclic AMP-Dependent Protein Kinase A Enhances SOX9's Ability To Transactivate aCol2a1 Chondrocyte-Specific Enhancer." Molecular and Cellular Biology 20, no. 11 (June 1, 2000): 4149–58. http://dx.doi.org/10.1128/mcb.20.11.4149-4158.2000.

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ABSTRACT Sox9 is a high-mobility-group domain-containing transcription factor required for chondrocyte differentiation and cartilage formation. We used a yeast two-hybrid method based on Son of Sevenless (SOS) recruitment to screen a chondrocyte cDNA library and found that the catalytic subunit of cyclic AMP (cAMP)-dependent protein kinase A (PKA-Cα) interacted specifically with SOX9. Next we found that two consensus PKA phosphorylation sites within SOX9 could be phosphorylated by PKA in vitro and that SOX9 could be phosphorylated by PKA-Cα in vivo. In COS-7 cells cotransfected with PKA-Cα and SOX9 expression plasmids, PKA enhanced the phosphorylation of wild-type SOX9 but did not affect phosphorylation of a SOX9 protein in which the two PKA phosphorylation sites (S64 and S211) were mutated. Using a phosphospecific antibody that specifically recognized SOX9 phosphorylated at serine 211, one of the two PKA phosphorylation sites, we demonstrated that addition of cAMP to chondrocytes strongly increased the phosphorylation of endogenous Sox9. In addition, immunohistochemistry of mouse embryo hind legs showed that Sox9 phosphorylated at serine 211 was principally localized in the prehypertrophic zone of the growth plate, corresponding to the major site of expression of the parathyroid hormone-related peptide (PTHrP) receptor. Since cAMP has previously been shown to effectively increase the mRNA levels of Col2a1 and other specific markers of chondrocyte differentiation in culture, we then asked whether PKA phosphorylation could modulate the activity of SOX9. Addition of 8-bromo-cAMP to chondrocytes in culture increased the activity of a transiently transfected SOX9-dependent 48-bp Col2a1chondrocyte-specific enhancer; similarly, cotransfection of PKA-Cα increased the activity of this enhancer. Mutations of the two PKA phosphorylation consensus sites of SOX9 markedly decreased the PKA-Cα activation of this enhancer by SOX9. PKA phosphorylation and the mutations in the consensus PKA phosphorylation sites of SOX9 did not alter its nuclear localization. In vitro phosphorylation of SOX9 by PKA resulted in more efficient DNA binding. We conclude that SOX9 is a target of cAMP signaling and that phosphorylation of SOX9 by PKA enhances its transcriptional and DNA-binding activity. Because PTHrP signaling is mediated by cAMP, our results support the hypothesis that Sox9 is a target of PTHrP signaling in the growth plate and that the increased activity of Sox9 might mediate the effect of PTHrP in maintaining the cells as nonhypertrophic chondrocytes.

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Wang, Jingyan, Xingyu Xie, Ying Deng, Hongqiu Yang, Xiaoshuang Du, Ping Liu, and Yu Du. "SOX9 in Keratinocytes Regulates Claudin 2 Transcription during Skin Aging." Contrast Media & Molecular Imaging 2022 (July 31, 2022): 1–13. http://dx.doi.org/10.1155/2022/6884308.

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In order to prove that SOX9 in keratinocytes regulates claudin 2 transcription during skin aging, the skin of 8-week-old and 24-month-old mice is sequenced to obtain a differentially expressed gene SOX9. The gene is mainly expressed in keratinocytes, and it increases first and then decreases from newborn to aging. Six core sequences of SOX9 and claudin 2 are predicted from Jaspar. The double Luciferase Report shows that overexpression of SOX9 induces the full-length promoter of claudin 2 significantly and has no effect on the mutation and cleavage plasmid without SOX9 response. Claudin 2 is consistent with SOX9 in the skin of mice of different ages, and SOX9 is strongly positively correlated with claudin 2. Finally, overexpression of SOX9 and claudin 2 will delay PM2.5-induced keratinocyte senescence. The silencing of claudin 2 leads to the loss of SOX9 function. It is clearly evident that SOX9 can affect the transcription of claudin 2, which increases first and then decreases in the process of mice from newborn to aging. SOX9 inhibits proinflammatory mediators, increases antioxidant capacity, and restores keratin differentiation. It can effectively prevent melanin deposition and delay aging.

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Kubo, Yusuke, Rainer Beckmann, Athanassios Fragoulis, Claudius Conrads, Prathyusha Pavanram, Sven Nebelung, Michael Wolf, Christoph Jan Wruck, Holger Jahr, and Thomas Pufe. "Nrf2/ARE Signaling Directly Regulates SOX9 to Potentially Alter Age-Dependent Cartilage Degeneration." Antioxidants 11, no. 2 (January 28, 2022): 263. http://dx.doi.org/10.3390/antiox11020263.

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Oxidative stress is implicated in osteoarthritis, and nuclear factor erythroid 2–related factor 2 (Nrf2)/antioxidant response element (ARE) pathway maintains redox homeostasis. We investigated whether Nrf2/ARE signaling controls SOX9. SOX9 expression in human C-28/I2 chondrocytes was measured by RT–qPCR after shRNA-mediated knockdown of Nrf2 or its antagonist the Kelch-like erythroid cell-derived protein with cap ‘‘n’’ collar homology-associated protein 1 (Keap1). To verify whether Nrf2 transcriptionally regulates SOX9, putative ARE-binding sites in the proximal SOX9 promoter region were inactivated, cloned into pGL3, and co-transfected with phRL–TK for dual-luciferase assays. SOX9 promoter activities without and with Nrf2-inducer methysticin were compared. Sox9 expression in articular chondrocytes was correlated to cartilage thickness and degeneration in wild-type (WT) and Nrf2-knockout mice. Nrf2-specific RNAi significantly decreased SOX9 expression, whereas Keap1-specific RNAi increased it. Putative ARE sites (ARE1, ARE2) were identified in the SOX9 promoter region. ARE2 mutagenesis significantly reduced SOX9 promoter activity, but ARE1 excision did not. Functional ARE2 site was essential for methysticin-mediated induction of SOX9 promoter activity. Young Nrf2-knockout mice revealed significantly lower Sox9-positive chondrocytes, and old Nrf2-knockout animals showed thinner cartilage and more cartilage degeneration. Our results suggest Nrf2 directly regulates SOX9 in articular cartilage, and Nrf2-loss can develop mild osteoarthritis at old age. Pharmacological Nrf2 induction may hold the potential to diminish age-dependent cartilage degeneration through improving SOX9 expression.

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Aldaz, Paula, Natalia Martín-Martín, Ander Saenz-Antoñanzas, Estefania Carrasco-Garcia, María Álvarez-Satta, Alejandro Elúa-Pinin, Steven M. Pollard, et al. "High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML." International Journal of Molecular Sciences 23, no. 9 (April 19, 2022): 4511. http://dx.doi.org/10.3390/ijms23094511.

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Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

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Wang, Chenqi, Jia Deng, Hao Deng, Zhiqian Kang, Zhen Huang, Zhi Ding, Lei Dong, Jiangning Chen, Junfeng Zhang, and Yuhui Zang. "A Novel Sox9/lncRNA H19 Axis Contributes to Hepatocyte Death and Liver Fibrosis." Toxicological Sciences 177, no. 1 (June 24, 2020): 214–25. http://dx.doi.org/10.1093/toxsci/kfaa097.

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Abstract Sox9 has been previously characterized as a transcription factor responsible for the extracellular matrix production during liver fibrosis. However, the deregulation and functional role of hepatocyte Sox9 in the progression of liver fibrosis remains elusive. Here, we found a significant increase of Sox9 in the hepatocytes isolated from CCl4-induced fibrotic liver and showed that antisense oligoribonucleotides depletion of Sox9 was sufficient to attenuate CCl4-induced liver fibrosis. Notably, the increase of Sox9 in hepatocyte was associated with the upregulation of long noncoding RNA H19 in both in vitro and in vivo systems. Mechanistic studies revealed that Sox9 induced H19 by binding to a conserved promoter region of H19. In vitro, hepatocyte injury triggered the increase of Sox9/H19 axis, whereas silence of H19 greatly alleviated the H2O2-induced hepatocyte apoptosis, suggesting that H19 functions as a downstream effector of Sox9 signaling and is involved in hepatocyte apoptosis. In animal experiments, inhibition of H19 alleviated the activation of hepatic stellate cells and reduced the extent of liver fibrosis, whereas ectopic expression of H19 abolished the inhibitory effects of Sox9 depletion on liver fibrosis, suggesting that the profibrotic effect of hepatocyte Sox9 depends on H19. Finally, we investigated the clinical relevance of Sox9/H19 axis to liver fibrosis and identified the increase of Sox9/H19 axis in liver cirrhosis patients. In conclusion, our findings link Sox9/H19 axis to the intrinsic mechanisms of hepatocyte apoptosis and may represent a hitherto unknown paradigm in hepatocyte injury associated with the progression of liver fibrosis.

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Dai, Ling, Yuqing Lu, Lu Jiang, Liping Zhu, Jing Zhang, Fang Wang, Yuanyuan Gao, and Wenwei Xin. "SRY-Box Transcription Factor 9 (SOX9) Affects the Proliferation, Invasion and Epithelial to Mesenchymal Transition (EMT) of Intrahepatic Cholangiocarcinoma by Regulating Transforming Growth Factor β (TGFβ)/Smad Signaling." Journal of Biomaterials and Tissue Engineering 11, no. 10 (October 1, 2021): 1891–99. http://dx.doi.org/10.1166/jbt.2021.2772.

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Intrahepatic cholangiocarcinoma (ICC) develops rapidly with a high malignancy. SOX9 expression is increased in several tumors. However, its expression and role in intrahepatic cholangiocarcinoma have not yet been elucidated. Real time PCR and Western blot were done to assess SOX9 expression in tumor tissues and adjacent tissues of ICC. ICC cell line QBC939 cells were separated into control group, SOX9 overexpression group and SOX9 siRNA group followed by analysis of cell survival by MTT assay, cell migration by cell scratch assay, cell invasion by transwell chamber, E-cadherin and Vimentin level by western blot, TGFβ/Smad signaling protein level by real time PCR. SOX9 level in tumor tissues was significantly increased compared to adjacent tissues (P < 0.05) and it was associated with TNM stage, tissue type and metastasis, and survival time (P < 0.05). Transfection of pcDNA3.1-SOX9 upregulated SOX9, promoted cell proliferation, migration and invasion, downregulated E-cadherin, upregulated Vimentin, TGF-β1 and Smad4 (P < 0.05). SOX9 siRNA transfection into QBC939 cells could significantly reverse the above mentioned changes (P < 0.05). SOX9 level is increased in intrahepatic cholangiocarcinoma and targeting SOX9 can inhibit cell migration and invasion, and EMT via regulating TGFβ/Smad signaling.

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Yang, Qing, Cheng Li, Manli Yan, and Chunhua Fang. "Effect of SOX9 on Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells Through WNTβ/Catenin Pathway." Journal of Biomaterials and Tissue Engineering 9, no. 10 (December 1, 2019): 1429–34. http://dx.doi.org/10.1166/jbt.2019.2140.

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Bone marrow mesenchymal stem cells (BMSCs) can be differentiated into different types of cells. SOX9 involves in the development and progression of various diseases. Our study aims to assess SOX9's effect on osteogenic differentiation of BMSCs and its related regulatory mechanisms. Rat BMSCs were isolated and randomly divided into control group, SOX9 group and SOX9 siRNA group, which was transfected with pcDNA-SOX9 plasmid or SOX9 siRNA respectively followed by analysis of SOX9 expression by Real time PCR, cell proliferation by MTT assay, Caspase3 and ALP activity, GSK-3β expression and Wntβ/Catenin Signaling pathway protein expression by Western blot, and expression of osteogenic genes Runx2 and BMP-2 by Real time PCR. Transfection of pcDNA-SOX9 plasmid into BMSCs significantly inhibited cell proliferation, promoted Caspase3 activity, decreased ALP activity and downregulated Runx2 and BMP-2, increased GSK-3β expression and decreased Wntβ/Catenin expression protein expression (P< 0.05). SOX9 siRNA transfection significantly promoted cell proliferation, inhibited Caspase3 activity, increased ALP activity and upregulated Runx2 and BMP-2, downregulated GSK-3β and increased Wntβ/Catenin expression. SOX9 regulates BMSCs proliferation and osteogenic differentiation through Wntβ/Catenin signaling pathway.

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Ma, Yanxia, David H. Hawke, Ganiraju Manyam, Wenyi Wang, Abhijit Mazumdar, and Powel Brown. "Abstract 2368: SOX9-binding proteins regulate SOX9 activity to control the growth of triple-negative breast cancer cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2368. http://dx.doi.org/10.1158/1538-7445.am2022-2368.

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Abstract Background: Triple-negative breast cancers (TNBCs) are the most aggressive types of breast cancer, which lack the expression of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR). TNBCs have a very poor prognosis and have few targeted therapy options. Therefore, the development of new TNBC treatment strategies is an urgent and unmet clinical need. Our previous studies have demonstrated that knockout of the SOX9 transcription factor decreased TNBC cell growth and tumor metastasis in vivo. Hypothesis: SOX9-binding proteins include upstream activators of this transcription factor which regulate SOX9 activity and control TNBC growth. Material and Methods: Immunoprecipitation (IP) in combination with mass spectrometry (IP-MS) analysis was used to identify SOX9 binding proteins, with support from MD Anderson’s proteomics core. The Mascot Score is a statistical score was used as the reference of targeted protein, and the data was summarized based on the Mascot Score. IP-Western Blotting analysis was used to confirm that the identified proteins bound SOX9 in TNBC cells. RNA-Seq analysis was used to identify SOX9 regulated genes in MDA MBA-231 and MDA MB-468 cells after SOX9 knockdown or in MCF-7 after SOX9 overexpression, with support from MD Anderson’s genomic biostatistics core. We then treated TNBC cells with or without siRNAs of these identified proteins to evaluate their effect on SOX9-regulated gene expression and TNBC growth. Cell growth was measured using an automated cell counting assay. Protein and mRNA levels were examined by western blotting and qRT-PCR assays. SOX9 transcriptional activity was measured using a reporter gene activity assay, and qRT-PCR assay. Data are presented as mean values ± SD. Statistical significance (p-values) was calculated using the Student’s t-test unless otherwise indicated. Results: Using immunoprecipitation in combination with mass spectrometry (IP-MS) analysis, we identified multiple SOX9 binding proteins. Among them, proteins that demonstrated high Mascot Scores include Valosin-Containing Protein (VCP), protein S100A10 (S100A10); Caveolin 1 (CAV1). Knockdown of each of these SOX9-binding proteins (VCP, S100A10, or CAV1) decreased TNBC cell growth in vitro. Using mRNA-Seq analysis, we next identified 38 genes down-regulated by SOX9 knockdown in TNBC cell lines, and up-regulated upon SOX9 overexpression in MCF-7 cells. Using these genes as markers of SOX9 transcriptional activity, all three of these SOX9-binding proteins regulate SOX9 activity. Thus, VCP, CAV1, and S100A10 all are potential upstream proteins of SOX9 that can be targeted to inhibit TNBC growth. Conclusion: Our results demonstrate that VCP, S100A10, and CAV1, are SOX9-binding proteins that regulate SOX9 activity and control TNBC cell growth. Implications: These proteins represent potential targets for the treatment of TNBCs. Citation Format: Yanxia Ma, David H. Hawke, Ganiraju Manyam, Wenyi Wang, Abhijit Mazumdar, Powel Brown. SOX9-binding proteins regulate SOX9 activity to control the growth of triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2368.

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Shen, Yajie, Jingqi Zhou, Kui Nie, Shuhua Cheng, Zhengming Chen, Wenhan Wang, Weiqing Wei, et al. "Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2+ diffuse large B-cell lymphomas." Blood 139, no. 1 (January 6, 2022): 73–86. http://dx.doi.org/10.1182/blood.2021012327.

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Abstract Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation–sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.

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Carrasco-Garcia, Estefania, Lidia Lopez, Veronica Moncho-Amor, Fernando Carazo, Paula Aldaz, Manuel Collado, Donald Bell, et al. "SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression." Cancers 14, no. 4 (February 12, 2022): 916. http://dx.doi.org/10.3390/cancers14040916.

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. Methods: We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. Results: Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. Conclusions: Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.

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Lefebvre, V., W. Huang, V. R. Harley, P. N. Goodfellow, and B. de Crombrugghe. "SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene." Molecular and Cellular Biology 17, no. 4 (April 1997): 2336–46. http://dx.doi.org/10.1128/mcb.17.4.2336.

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The identification of mutations in the SRY-related SOX9 gene in patients with campomelic dysplasia, a severe skeletal malformation syndrome, and the abundant expression of Sox9 in mouse chondroprogenitor cells and fully differentiated chondrocytes during embryonic development have suggested the hypothesis that SOX9 might play a role in chondrogenesis. Our previous experiments with the gene (Col2a1) for collagen II, an early and abundant marker of chondrocyte differentiation, identified a minimal DNA element in intron 1 which directs chondrocyte-specific expression in transgenic mice. This element is also a strong chondrocyte-specific enhancer in transient transfection experiments. We show here that Col2a1 expression is closely correlated with high levels of SOX9 RNA and protein in chondrocytes. Our experiments indicate that the minimal Col2a1 enhancer is a direct target for Sox9. Indeed, SOX9 binds to a sequence of the minimal Col2a1 enhancer that is essential for activity in chondrocytes, and SOX9 acts as a potent activator of this enhancer in cotransfection experiments in nonchondrocytic cells. Mutations in the enhancer that prevent binding of SOX9 abolish enhancer activity in chondrocytes and suppress enhancer activation by SOX9 in nonchondrocytic cells. Other SOX family members are ineffective. Expression of a truncated SOX9 protein lacking the transactivation domain but retaining DNA-binding activity interferes with enhancer activation by full-length SOX9 in fibroblasts and inhibits enhancer activity in chondrocytes. Our results strongly suggest a model whereby SOX9 is involved in the control of the cell-specific activation of COL2A1 in chondrocytes, an essential component of the differentiation program of these cells. We speculate that in campomelic dysplasia a decrease in SOX9 activity would inhibit production of collagen II, and eventually other cartilage matrix proteins, leading to major skeletal anomalies.

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Ramalingam, S., G. W. Daughtridge, M. J. Johnston, A. D. Gracz, and S. T. Magness. "Distinct levels of Sox9 expression mark colon epithelial stem cells that form colonoids in culture." American Journal of Physiology-Gastrointestinal and Liver Physiology 302, no. 1 (January 2012): G10—G20. http://dx.doi.org/10.1152/ajpgi.00277.2011.

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Sox9 is an high-mobility group box transcription factor that is expressed in the stem cell zone of the small intestine and colon. We have previously used a Sox9EGFP mouse model to demonstrate that discrete levels of Sox9 expression mark small intestine epithelial stem cells that form crypt/villus-like structures in a three-dimensional culture system (Formeister EJ, Sionas AL, Lorance DK, Barkley CL, Lee GH, Magness ST. Am J Physiol Gastrointest Liver Physiol 296: G1108–G1118, 2009; Gracz AD, Ramalingam S, Magness ST. Am J Physiol Gastrointest Liver Physiol 298: G590–G600, 2010). In the present study, we hypothesized that discrete levels of Sox9 expression would also mark colonic epithelial stem cells (CESCs). Using the Sox9EGFP mouse model, we show that lower levels of Sox9 mark cells in the transit-amplifying progenitor cell zone, while higher levels of Sox9 mark cells in the colonic crypt base. Furthermore, we demonstrate that variable SOX9 levels persist in cells of colonic adenomas from mice and humans. Cells expressing lower Sox9 levels demonstrate gene expression profiles consistent with more differentiated populations, and cells expressing higher Sox9 levels are consistent with less differentiated populations. When placed in culture, cells expressing the highest levels of Sox9 formed “colonoids,” which are defined as bodies of cultured colonic epithelial cells that possess multiple cryptlike structures and a pseudolumen. Cells expressing the highest levels of Sox9 also demonstrate multipotency and self-renewal in vitro, indicating functional stemness. These data suggest a dose-dependent role for Sox9 in normal CESCs and cells comprising colon tumors. Furthermore, distinct Sox9 levels represent a new biomarker to study CESC and progenitor biology in physiological and disease states.

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Kent, J., S. C. Wheatley, J. E. Andrews, A. H. Sinclair, and P. Koopman. "A male-specific role for SOX9 in vertebrate sex determination." Development 122, no. 9 (September 1, 1996): 2813–22. http://dx.doi.org/10.1242/dev.122.9.2813.

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Mutation analyses of patients with campomelic dysplasia, a bone dysmorphology and XY sex reversal syndrome, indicate that the SRY-related gene SOX9 is involved in both skeletal development and sex determination. To clarify the role SOX9 plays in vertebrate sex determination, we have investigated its expression during gonad development in mouse and chicken embryos. In the mouse, high levels of Sox9 mRNA were found in male (XY) but not female (XX) genital ridges, and were localised to the sex cords of the developing testis. Purified fetal germ cells lacked Sox9 expression, indicating that Sox9 expression is specific to the Sertoli cell lineage. Sex specificity of SOX9 protein expression was confirmed using a polyclonal antiserum. The timing and cell-type specificity of Sox9 expression suggests that Sox9 may be directly regulated by SRY. Male-specific expression of cSOX9 mRNA during the sex determination period was also observed in chicken genital ridges. The conservation of sexually dimorphic expression in two vertebrate classes which have significant differences in their sex determination mechanisms, points to a fundamental role for SOX9 in testis determination in vertebrates. Sox9 expression was maintained in the mouse testis during fetal and adult life, but no expression was seen at any stage by in situ hybridisation in the developing ovary. Male-specific expression was also observed in the cells surrounding the Mullerian ducts and in the epididymis, and expression in both sexes was detected in the developing collecting ducts of the metanephric kidney. These results suggest that SOX9 may have a wider role in the development of the genitourinary system.

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Stöckl, Sabine, Georg Lindner, Shushan Li, Philipp Schuster, Sebastian Haferkamp, Ferdinand Wagner, Peter M. Prodinger, et al. "SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line." International Journal of Molecular Sciences 21, no. 20 (October 15, 2020): 7627. http://dx.doi.org/10.3390/ijms21207627.

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As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies. Our study shows an increase in SOX9 expression in chondrosarcoma compared to normal cartilage, but a decrease when the tumors are finally defined as dedifferentiated chondrosarcoma (DDCS). In DDCS, SOX9 is almost completely absent in the non-chondroid, dedifferentiated compartments. CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13. In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin. The siRNA-mediated SOX9 knockdown partially confirmed these results, suggesting the need for a certain SOX9 threshold for particular cancer-related events. To increase the efficacy of chondrosarcoma therapies, potential therapeutic approaches were analyzed in SOX9 knockout cells. Here, we found an increased impact of doxorubicin, but a reduced sensitivity for oncolytic virus treatment. Our observations present novel insight into the role of SOX9 in chondrosarcoma biology and could thereby help to overcome the obstacle of drug resistance and limited therapy options.

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Xue, Yue, Wenwen Lian, Jiaqi Zhi, Wenjuan Yang, Qianjin Li, Xingyi Guo, Jiahao Gao, et al. "HDAC5-mediated deacetylation and nuclear localisation of SOX9 is critical for tamoxifen resistance in breast cancer." British Journal of Cancer 121, no. 12 (November 6, 2019): 1039–49. http://dx.doi.org/10.1038/s41416-019-0625-0.

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Abstract Background Tamoxifen resistance remains a significant clinical challenge for the therapy of ER-positive breast cancer. It has been reported that the upregulation of transcription factor SOX9 in ER+ recurrent cancer is sufficient for tamoxifen resistance. However, the mechanisms underlying the regulation of SOX9 remain largely unknown. Methods The acetylation level of SOX9 was detected by immunoprecipitation and western blotting. The expressions of HDACs and SIRTs were evaluated by qRT-PCR. Cell growth was measured by performing MTT assay. ALDH-positive breast cancer stem cells were evaluated by flow cytometry. Interaction between HDAC5 and SOX9 was determined by immunoprecipitation assay. Results Deacetylation is required for SOX9 nuclear translocation in tamoxifen-resistant breast cancer cells. Furthermore, HDAC5 is the key deacetylase responsible for SOX9 deacetylation and subsequent nuclear translocation. In addition, the transcription factor C-MYC directly promotes the expression of HDAC5 in tamoxifen resistant breast cancer cells. For clinical relevance, high SOX9 and HDAC5 expression are associated with lower survival rates in breast cancer patients treated with tamoxifen. Conclusions This study reveals that HDAC5 regulated by C-MYC is essential for SOX9 deacetylation and nuclear localisation, which is critical for tamoxifen resistance. These results indicate a potential therapy strategy for ER+ breast cancer by targeting C-MYC/HDAC5/SOX9 axis.

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Journal articles on the topic 'Sox9b'

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