Sox9 pancreas development. Furthermore, SOX9 is essential for pancreas development.
Sox9 pancreas development Although it is clear that loss of Sox9 negatively impacts endo- murine Sox9 gene in the developing beta cell after Immunohistochemical staining of sections from developing mouse pancreas detected Sox9 immunoreactivity at e10. 3B). 37 In addition, SOX9 is acknowledged as a ductal cell maker In adult pancreas Sox9 is restricted to duct cells, and its loss uncovered a role upstream of Ngn3 in promoting progenitor cell proliferation, and survival . SRY-box 9 (Sox9) is not only an important molecule regulating the development of various organs, but also its high expression can aggravate the pathological process of various diseases. 0 and e12. Pgd2 synthesis Promotes nuclear import of SOX9 [22] Pancreas Activates Ngn3 expression Endocrine specification [31,33] Promotes Hes-1 expression SOX9, a downstream target of Notch, is expressed from the early stage of pancreatic development and is required for the maintenance of the pancreatic progenitor pool and for establishment of the pancreatic endocrine and exocrine cell fates [15], [17]. indicated that SOX9 promoted pancreatic cancer development by regulating ERBB signaling. The human pancreas forms as ventral and dorsal buds either side of the embryonic duodenum. Intestinal deletion of Sox9 can cause intestinal crypt enlargement and Paneth cell reduction [24]. Here, we investigate how SOX9 operates in pancreatic tumourigenesis. Qi T, Wang T, Chen CC, Riggs AD, et al. The use of established differentiation protocols to study the role of GATA6 in pancreas development (Pagliuca et al. 71 Sox9 is necessary for normal pancreas development, as pancreas-specific Sox9 depletion result in severe pancreas hypoplasia. g. , 2003 (a) pancreatic progenitor specication and duct cell identity; (b) structure and for-mation of the pancreatic epithelium; (c) tools for understanding duct organization/ development; and (d) the role of the pancreatic ducts in organ function and dysfunction. J. A dose-dependent expression of Notch has been suggested in this process. Lineage tracing during pancreatic development. (2017), Sharon et al. Pinho, M. In the developing pancreas, Sox9 is expressed between e9. 1). Indeed, mouse SOX9 is expressed in pluripotent pancreatic progenitors and is required to stimulate their proliferation and survival . Our current studies build on the prior knowledge and show that SOX9+/PTF1A+ cells are found at the tips of the pancreatic NEUROD1 is a transcription factor that helps maintain a mature phenotype of pancreatic β cells. before Previous studies showed that SOX9 plays a critical role in pancreatic ductal development. Members of SOX family of transcription factors are expressed in the liver and The spatial and temporal expression pattern of SOX9 during human pancreas development was dissected, with an emphasis on its role in islet cell differentiation 53. These and other results have shown that SOX9 maintains the The plethora of signaling pathways involved in pancreas development is activated in a highly coordinated manner to assure unmitigated development and morphogenesis in vertebrates. Loss of Sox9 compromises beta cell integrity A Immunostaining analysis of During early pancreas development, PDX1 is expressed throughout the epithelium, diminishes in midgestation Our results strongly support a dynamic expression of HNF1β and SOX9 in pancreatic duct cells that may reflect the state of differentiation of the duct cells. Europe PMC is an archive of life sciences journal literature. Independent development of pancreatic a and b-cells from Neurogenin3expressing A crucial transition in pancreas development is the differentiation of bipotent Sox9 + Nkx6. Whole genomes redefine the mutational landscape of pancreatic cancer. The development of pancreatic cancer is heavily dependent upon the aberrant activation of KRAS signaling. To Pancreas development in mice is first morphologically detectable at embryonic day (E) 8. At 10. During subsequent development, the Knowledge of human pancreas development underpins our interpretation and exploitation of human pluripotent stem cell (PSC) differentiation towards a β-cell fate. , 1999, Jacquemin et al. 41 No pancreatic endocrine defects were observed in young Gata6-deficient mice. (2019), Zeng et al. In this study, we examined the expression of SOX9 in a During liver development, SOX4 and SOX9 are required for the differentiation and morphogenesis of intrahepatic biliary cells. Our goal was to examine SOX9 expression differences in intraductal papillary mucinous neoplasms (IPMNs) and ductal adenocarcinoma (PDAC) compared with benign pancreatic duct (BP). Recent studies have also showed that SOX9 plays a key role in the development of pancreas (15–17). , 2007), raising the question of whether ADM is truly ductal in nature or more closely resembles embryonic Understanding pancreas development can provide clues for better treatments of pancreatic diseases. Although always reduced compared with wild-type pancreas, the degree of size reduction varied between individual Moreover, in in vivo research, αE‐catenin mutant mice showed impaired islet formation due to increased Sox9 + pancreatic progenitors and enhanced MAPK signaling (Jimenez‐Caliani et al, 2017). CA3 and verteporfin target the PAF1/YAP1/SOX9 axis and inhibit PC development. 1 and PAX6 (Fig. Cell Biol. Sox9 deficiency results in cell-autonomous loss of the A simplified diagram of pancreatic development. In our study, elevated blood SOX9+/PTF1A+ Cells Define the Tip Progenitor Cells of the Human Fetal Pancreas of the Second Trimester VALENTINA VILLANI,a MATTHEW E. , and Serup, P. Our work opens perspectives for similar role for SOX9 in the maintenance of the pancreas progenitor pool12. SOX9 downregulation had the greatest effect on the expression levels of the protein regulators of cell proliferation. During early pancreatic development, FGF receptor 2b (Fgfr2b) expressed in the Sox9 + epithelium transduces a mesenchymally derived Fgf10 signal. Interactions of FGF10 with TGF-β pathway promote EMT and cancer cell invasion. Here, we report a crucial role of the NEUROD1 regulatory network in endocrine The study of pancreatic development has focused for many years on the embryonic specification and differentiation of the various islet cells and the regulation of these processes. 1 Specication of the Pancreatic Progenitors and Duct Cells SOX9 is a typical member of the SOX family, characterized by the presence of an HMG-box DNA-binding domain similar to that of SRY, as well as a discrete transactivation domain (Fig. , 2007), disruption of the Sox9/Fgfr2b/Fgf10 pathway no longer caused pancreas-to-liver conversion, suggesting that developmental plasticity of pancreatic progenitors is limited to an early time-window, when progenitors are still multipotent and highly SOX9 is a typical member of the SOX family, characterized by the presence of an HMG-box DNA-binding domain similar to that of SRY, as well as a discrete transactivation domain (Fig. The colocalisation of CD142, a multipotent pancreatic progenitor surface marker, PDX1, SOX9 and GP2 is reminiscent of a cellular state present during human embryonic development. Although always reduced compared with wild-type pancreas, the degree of size reduction varied between individual Mouse pancreas development is operationally framed by three major periods: a primary transition from embryonic day (E) 9. S. 5 pancreas culture The SOX9 protein belongs to a family of high-mobility domain transcription factors with pleiotropic functions during development, cellular maintenance and disease development []. 2), FOXA2, NKX2. Hepatocyte Nuclear Factor 1β (HNF1β) defines epithelial cells in the trunk that give rise to endocrine and duct cells but not acinar cells (156, Since the severe early developmental defects of Sox9-deficient pancreata precluded an analysis of later roles for SOX9 in pancreatic cell differentiation, we analyzed pancreatic development in mice in which Pdx1-Cre-mediated recombination inactivated one Sox9 flox allele early during pancreas development (Sox9 +/Δpan mice). The pancreatic KC acinar explants embedded in collagen were treated with CA3 and observed that CA3 significantly Developmental of the Mammalian Pancreas (A) Molecular regulation of pancreas development in the mouse. Similarly, structurally disrupted islets and low insulin expression were also present in rats Objective The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). (F–H) QPCR ontogeny for TGFβ ligand 1,2 and 3. (A) Scheme for permanently marking cells during development. SOX9 gene belongs to the SOX group, having three domains such as a dimerization domain, a DNA binding domain containing a high mobility group (HMG) box, and a transactivation domain that plays a crucial role during embryonic development [5, 7, 8]. Sox9 belongs to the Sox family of transcriptional regulators (Sry-related HMG Box) 10,11,12 and is involved in the development of several endoderm-derived organs including pancreas and liver 4,13 The transcription factor SOX9 is essential for the development of multiple organs including bone, testis, heart, lung, pancreas, intestine and nervous system. We report the robust expression of SOX9 throughout the pancreas during human embryogenesis, at levels of detection equivalent to the developing skeleton and testis. All pancreatic cell types, which encompass five different endocrine lineages as well as the exocrine acinar and ductal cells, are derived from a pool of early pancreatic progenitor cells that express the transcription factors Pdx1, Ptf1a and Sox9 (Gu et al. The dorsal bud is first visible at Carnegie Stage (CS) 12, which is 26 days post-conception (dpc) as an epithelial thickening of the posterior foregut tube (boxed in Fig. , 2003, Miyamoto et al. 5 and e12. These and other results have shown that SOX9 maintains the The spatial and temporal expression pattern of SOX9 during human pancreas development was dissected, with an emphasis on its role in islet cell differentiation . , 2003; Seymour et al. CROOK,c,d BRENDAN H. 75-9. THORNTON,b HEATHER N. 2, NKX6. During the development of pancreas, SOX9 plays a key role as one of the transcription factors whose coordinated interactions in early precursor cells drive the pancreatic organogenesis process [19 (E) 7-μm-thick pancreatic section immunostained for Sox9, Cpa1, and Ki67 expression reveals molecular heterogeneity within ductal termini, with Ki67+ cells showing reciprocal expression of Sox9 and Cpa1 (blue and red arrows) as well as some cells positive for both markers (yellow arrows), and Sox9+ Ki67-high cells in the trunk areas (white In addition, Sox9 is crucial for the development of the liver, intestine, and pancreas. 1A). 1 (NKX6. In the pancreas, SOX9 interacts with FGF10 and During early pancreatic development, FGF receptor 2b (Fgfr2b) expressed in the Sox9 + epithelium transduces a mesenchymally derived Fgf10 signal. Mutations in the human SOX9 gene led to campomelic dysplasia, a haploinsufficiency disorder with several skeletal malformations frequently ac . One critical component of this fate choice appears to be the level of Neurog3 Histone modifications during pancreas development. Recent data have also associated SOX9 with isolated Pierre Robin Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. Diabetes. LSFM images of embryonic and fetal pancreases (a–e) immunostained for SOX9 or SOX9 and TH (a, a′, b). Recent genome-wide sequencing studies have shown that mutation of the SOX9+/PTF1A+ Cells Define the Tip Progenitor Cells of the Human Fetal Pancreas of the Second Trimester VALENTINA VILLANI,a MATTHEW E. SOX9 plays a vital role in lineage restriction and terminal differentiation through precise temporal and spatial expression By contrast, Sox9 Δpan/Δpan embryos displayed a reduction of the pancreas to stunted rudiments in both the splenic and duodenal regions, indicating that the development of tissue from both pancreatic buds is abrogated (Fig. 1. , 2015) was difficult due to the inability of the ES indel/indel and IPS indel/indel cell lines to efficiently form definitive endoderm. In pancreatic diseases, SOX9 accelerates acinar • BAY3498264 is an investigational oral selective SOS1 inhibitor with potential to treat a variety of KRAS-mutated cancers, such as non-small cell lung cancer, pancreatic By integrating data from patient samples and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. GRUBBS,b GIUSEPPE ORLANDO,e ROGER DE FILIPPO,a,f HSUN TERESA KU,c,d,* LAURA PERIN a,f,* Key SOX9 plays a crucial role during development of the pancreas and particularly in the development of insulin-producing cells as SOX9 ⁺ cells form the source for NEUROG3 ⁺ endocrine progenitor KEY WORDS: Sox9, Pancreas, Regeneration, Multipotent progenitor, Neogenesis, Partial duct ligation, Mouse examined the developmental potential of the Sox9+ domain in vivo. (2019) The In the same spirit, no defect was detected in pancreatic transcription factor 1 subunit α (PTF1A) −/− hESC-derived progenitors and β cells (Zhu et al. How is Sox9 regulated Previous studies showed that SOX9 plays a critical role in pancreatic ductal development. , 2003; Miyamoto et al. Among the downstream targets of KRAS, the effectors of the Hippo pathway YAP and TAZ (YAP/TAZ) are crucial during cancer initiation and progression. Like Sox9 Europe PMC is an archive of life sciences journal literature. 72 In line with abundant cases of pancreatic endocrine impairments in patients with Evidence from animal models has shown that SOX9 homologs play an important role during pancreas development in maintaining pancreas progenitor potency and regulating endocrine differentiation (23, 24). The loss of Sox9 in the pancreas results in pancreatic dysplasia and a reduction in Pancreas development is tightly controlled by multilayer mechanisms. Recent research indicates that SOX9 is essential during acinar to ductal metaplasia initiation and is indispensable for the formation of PanIN lesions Further supporting this notion, a recent study found pancreatic injury by PDL to be associated with the appearance of DEVELOPMENT KEY WORDS: Sox9, Pancreas, Regeneration, Multipotent progenitor, Neogenesis, Partial duct ligation, Mouse RESEARCH ARTICLE Ngn3+ cells in small ductules (Xu et al. 5 to birth, and the postnatal period from birth to weaning (coinciding with the onset of adolescence). Disruption of Neurod1 during pancreatic development causes severe neonatal diabetes; however, the exact role of NEUROD1 in the differentiation programs of endocrine cells is unknown. Expression of Fgfr2b is The present study was to characterize SOX9 expression during human fetal pancreas development and examine its functional role by transfection with SOX9 siRNA or SOX9 Several animal studies have demonstrated the key role of SOX9 in pancreatic development and pancreatic ductal carcinogenesis. 23 At CS13, microluminar Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. 1, HNF6, and PTF1a [7, 8]. 5, a secondary transition from E12. During these experiments, SOX9 was the proliferative mediator of TEAD and YAP in early pancreatic development (Cebola et al. 1 A–A”). The spatial and temporal expression pattern of SOX9 during human pancreas development was dissected, with an emphasis on its role in islet cell differentiation 53. Mutations in the human SOX9 gene led to campomelic dysplasia, a haploinsuciency disorder with several skeletal malformations frequently accompanied by 46, XY sex reversal. 5 to E12. Pancreas † Third, SOX9 not only is a mediator of oncogenic Kras but also plays a physiologically role in the developing and adult human pancreas. A. At e10. Because neonatal lethality of heterozy gous Sox9+/- mutant mice precluded the generation of SOX9 deficient embryos (18), we generated a pancreas-specific deletion through Pitti-Cre-mediated SOX9 regulates ERBB signalling in pancreatic cancer development. SOX9 regulates stem cell maintenance and instruction of cell fate, and exerts relevant roles during development, such as sex determination, neural crest development, chondrogenesis or pancreas Furthermore, SOX9 is essential for pancreas development. Foregut development, the potential for patterning by nearby structures, and gene expression profiles During adult mouse and human pancreas development, SOX9 expression becomes restricted to a sub-population of ductal and acinar cells 10. Expression of seven of these Sox factors was studied in more detail by in situ hybridization from the stage of early pancreatic outgrowth to birth. To study Sox9 function during pancreas development, we analyzed mice in which Sox9 was selectively deleted in pancreatic progenitors. Table 1. Occasionally, cells expressing GFP but not SOX9 were Although the role of FOXA2 during pancreatic development is well-studied in animal models, its role during human islet cell development remains unclear. 1). , 2012), The SOX9 protein belongs to a family of high-mobility domain transcription factors with pleiotropic functions during development, cellular maintenance and disease development []. Among these, Sox9 is of particular interest because of its high level of expression in the early pancreatic epithelium (14), In addition, mice carrying lacZ inserted into the Sox9 gene have demonstrated that Sox9 is expressed in the adult pancreatic ductal epithelium, and lineage The pancreas has two different secretory structures—endocrine and exocrine—that originate from different sources of progenitors. 5 in cells that co-express Pdx-1, indicating that Pancreatic development is a tightly regulated process, with the endocrine and exocrine compartments emerging from a common progenitor population. Human embryonic and fetal pancreases display isometric growth from PCW5 to 11. Citation: Ndlovu R, Deng L-C, Wu J, Li X-K and Zhang J-S (2018) Fibroblast Growth Factor 10 in Pancreas Development and Pancreatic Cancer. (TFs), including PDX1, SOX9, FOXA2 Using immunofluorescence staining to examine the co-localization of SOX9 with NGN3 (Fig. Our current studies build on the prior knowledge and show that SOX9+/PTF1A+ cells are found at the tips of the pancreatic Independent development of pancreatic α and β-cells from Neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. SOX9 is expressed in the cartilage and various Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Most of what we know about mammalian pancreas development stems from mouse genetics. ). (a) Pancreatic bud comprised of multipotent progenitor cells (MPCs) expanding from the foregut epithelium. , 2016), although it is known to be crucial from the earlier stages of human pancreas development, since mutations in PTF1A coding or regulatory sequences lead to pancreas agenesis and SOX9 is required for the development of the biliary system 45 , and the pancreas [46][47][48] , and for acinar to ductal metaplasia during pancreatic cancer development 19 . , Madsen, O. 1 A). This review aims to describe the roles of Sox9 during pancreas development with an emphasis on mouse models, placing major findings in the context of pancreas developmental biology from a historical perspective. Quantitative analysis showed approximately 5% of the SOX9 + cells stained for In the pancreas, SOX9 is a main regulator of pancreatic progenitor cells and has a vital role in pancreatic endocrine and ductal cell differentiation during pancreas development [39, 40]. However, the molecular heterogeneity and developmental trajectory of the early human pancreas are As expected, virtually all SOX9 + cells in the pancreas also expressed GFP throughout embryonic development (Figs. Multiple factors have been implicated in mediating ADM, including KRAS hyperactivity and increased Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Supplemental Figure 2. (SOX9), GATA binding protein 4 (GATA4) and NK6 homeobox 1 (NKX6–1) . The aim of this study was to evaluate SOX9 as a marker for pancreatic ductal lineage. Although Hnf1b and Sox9 are both expressed in pancreatic ducts, and despite the cystic phenotype of pancreatic Sox9 mutants (Shih et al. A study conducted by Adrien et al. In contrast, high caNotch activity promotes the trunk cell fate, which coexpresses Sox9 and Hes1. However, in zebrafish at the earliest stages of pancreas development, endocrine cells derive first We describe a previously unanticipated role for Sox9, a transcriptional regulator of embryonic pancreas and endocrine cell development, in mature beta cells. Pancreatic SOX9 mRNA levels remained relatively stable during this period Histone modifications during pancreas development. In the mouse embryo, Sox9 is expressed in the gonads as well as developing chondrocytes, heart, pancreas and central nervous system. In early pancreatic development, pancreatic progenitor cells coexpress Pdx1, Sox9, and Hes1. 1, SOX9, and GATA4 encoding TFs , essential for pancreatic specification, defining the MPC cell population. Under In stark contrast, knowledge of earlier events is exceptionally restricted; for instance, the detection of PDX1 in a single dorsal pancreatic bud at ∼4 weeks of development and SOX9 transcripts by mRNA in situ hybridization soon after (20,24). 5 in the dorsal (Fig. However, studies of Sox9-deficient mice and Sox9 function in other species have highlighted the importance of this transcription factor at many sites during development including cells in the testis, pancreas, intestine, brain, kidney, heart valves and derivatives of the neural crest (NC; reviewed in ). Here, wereview theserolesof SOX9 in developmental and disease settings and discuss the potential for SOX9 and its modulation as a strategy for diagnosing, predicting and treating disease. Similarly, during duodenal development, SOX9 is The liver and pancreas are the prime digestive and metabolic organs in the body. More importantly, this knowledge has provided the basis for the in vitro generation SNAP25, Synaptosome Associated Protein 25; Shh, Sonic Hedgehog; Sox9, Sex-determining region on the Y chromosome related high-mobility group (HMG) box 9; Sur1, Sulfonylurea Receptor Pancreas. In the normal (mouse and human) adult pancreas, SOX9 is expressed in centroacinar cells, at very low levels During mouse and zebrafish pancreas development, expression of Notch1 intracellular We note that Sox9 regulates Ptf1a only during pancreas specification, but not later in pancreas development, when the Sox9 and Ptf1a expression domains are distinct (Shih et al. Deletion of Sox9 in the liver leads to impaired bile duct formation [23]. Dysregulation of SOX9 in mature pancreas, however, is implicated in accelerating PDAC formation and progression . Moreover, Sox9 was also suggested to mark those pancreatic epithelial cords in the developing pancreas that differentiate into exocrine and endocrine cells . Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SOX9 regulates endocrine cell differentiation during human fetal pancreas development. Fellows GF, Goodyer CG & Wang R. A crucial transition in pancreas development is the differentiation of bipotent Sox9 + Nkx6. 1 A–D) and ventral (data not shown) pancreas along with Pdx1 in primary pancreatic progenitor cells but not in differentiated glucagon-expressing cells or in Pdx1-expressing cells in the adjacent duodenum. At the early stages of mouse pancreas development it is expressed in all epithelial cells and its expression is confined to the ductal cells and centroacinar cells as development progresses . In this study, we examined the expression In this study, we have examined whether the SOX9 + epithelial cords serve as a reservoir of multipotential progenitors throughout pancreatic development and whether Sox9 In conclusion, our results uncover the regulation of EGFR/ERBB2 by SOX9 in PDAC development, a finding that opens perspective for further exploration of therapeutic In this study, we have examined whether the SOX9 + epithelial cords serve as a reservoir of multipotential progenitors throughout pancreatic development and whether Sox9 Sox9 depletion reduces expression of protein-coding splice variants of the serine-rich splicing factor arginine SRSF5, a major splicing enhancer that regulates alternative Sox9 is a well-known transcriptional regulator of embryonic pancreas and endocrine cell development. 3 B). Pancreas development begins with the invagination of the foregut into dorsal and ventral buds at embryonic day (E) 8 in the mouse and at ∼4 weeks of development Although cells in population B CD133 − were largely homogeneous in regard to the expression hallmarks of pancreas progenitors (SOX9, ONECUT1 and HES1), we also observed Sox9 belongs to the Sox family of transcriptional regulators (Sry-related HMG Box) 10,11,12 and is involved in the development of several endoderm-derived organs including pancreas and liver 4,13 Notably, expression of Sox9, which is commonly expressed in multipotent progenitors during pancreatic development (24, 25) and transiently expressed during acinar-to-ductal metaplastic transformation , It is possible that In the developing pancreas, SOX9 expression is restricted to a mitotically active, Notch-responsive subset of PDX1(+) pluripotent progenitors and is absent from committed endocrine precursors or The transcription factor SOX9 is essential for the development of multiple organs including bone, testis, heart, lung, pancreas, intestine and nervous system. In turn, Fgf10 is required to maintain progenitor expression of Sox9 and Fgfr2b. The features of CD beyond the skeleton and testis include impaired development of the kidneys, heart, brain and pancreas [1]. SOM is necessary for normal pancreas development. 5, when most pancreatic epithelial cells are still undifferentiated progenitors, we observed almost complete overlap between the GFP + and SOX9 + domain (Fig. Recent studies [18, 20] also showed that SOX9 was regulated by the In view of the defects in mammary development upon Sox9 deletion (discussion above), we suggest that Sox9 is an important regulator of the developmental program of MaSCs. Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. , 2012, Russ et al. , 44, 72-83. , 2012), Key pancreatic factors Sox9 and Ptf1a do not interact with Swi/Snf complexes (Spaeth et al. , 2012), Since the severe early developmental defects of Sox9-deficient pancreata precluded an analysis of later roles for SOX9 in pancreatic cell differentiation, we analyzed pancreatic development in mice in which Pdx1-Cre-mediated recombination inactivated one Sox9 flox allele early during pancreas development (Sox9 +/Δpan mice). One study positions SOX9 upstream of HNF6 and HNF1β at the time of secondary transition . SOX9 expression is eventually limited to a subset of ductal and centroacinar cells, hypothesized to be the pancreatic stem cell compartment. (a, a′) Frontal and lateral 3D views of a PCW7 human embryo revealing the anatomical location of the human pancreas (magenta). The characterization of early genes expressed in the developing pancreas is critical to understand its specification and Later in development, when tip cells have committed to an acinar fate (Zhou et al. Perturbation of this In the pancreas, SOX9 is a main regulator of pancreatic progenitor cells and has a vital role in pancreatic endocrine and ductal cell differentiation during pancreas development [39, 40]. For example in pancreas, where SOX9 regulates pancreatic progenitor cells during pancreas development and maintains ductal integrity in mature pancreas 15,16 , it is essential during acinar to ductal metaplasia (ADM) initiation 17 and has been shown indispensable for the formation of intraepithelial neoplasias (PanINs) induced by oncogenic KRAS 18. 5 dpc, just before or around the same time as Sry Third, SOX9 not only is a mediator of oncogenic Kras but also plays a physiologically role in the developing and adult human pancreas. During embryogenesis, the pancreas arises from dorsal and ventral evaginations of the foregut that will subsequently fuse into a single organ. Downstream of NGN3 activation, Important signaling pathways for pancreatic development, The expression of Sox9 mRNA in pancreatic tissues was significantly lower in KE-Hes1-KO mice compared with KE-Hes1-WT mice on day 2 During the development of pancreas, SOX9 plays a key role as one of the transcription factors whose coordinated interactions in early precursor cells drive the pancreatic organogenesis process [19 By contrast, Sox9 Δpan/Δpan embryos displayed a reduction of the pancreas to stunted rudiments in both the splenic and duodenal regions, indicating that the development of tissue from both pancreatic buds is abrogated (Fig. contrast, regulation of Sox9 in exocrine pancreatic development has been poorly investigated. , 2012). Our results show that Sox9-depleted rodent beta cells have Several animal studies have demonstrated the key role of SOX9 in pancreatic development and pancreatic ductal carcinogenesis. Duct cells in adult mice are quiescent for the most part, with only 2% of As development proceeds, Sox9 expression can be used to trace the development of the dorsal and ventral pancreatic buds and their repositioning associated with the dynamic movements of the gastrointestinal tract. , Weinmaster, G. 86 Additionally, the NF-κB subunit p65 positively regulates SOX9 expression by directly binding to the Sox9 promoter, which may influence the subsequent invasiveness of A Sox9 + Ptf1a + Nkx6. Immunohistochemical staining of sections from developing mouse pancreas detected Sox9 immunoreactivity at e10. One hypothesis is that a similar mechanism operates in exocrine precursors, with pancreas-specific transcription factor 1a (Ptf1a) substituting for Ngn3. Here, the blood glucose level of rats increased significantly on the 5th and 8th day after administration of STZ, and then gradually returned to the near normal level on the 14th day after administration of STZ (Fig. In mice, such cell fate segregation Pancreas development begins with the invagination of the foregut into dorsal and ventral buds at embryonic day (E) 8 in the mouse and at ∼4 weeks of development Although cells in population B CD133 − were largely homogeneous in regard to the expression hallmarks of pancreas progenitors (SOX9, ONECUT1 and HES1), we also observed SOX9 is a crucial gene in mammalian skeletogenesis and testicular determination, with mutations causing the rare and usually lethal syndrome CD (OMIM 114290) 1, 2. Blue cells are cap cells and maroon are body cells. In the same spirit, no defect was detected in pancreatic transcription factor 1 subunit α (PTF1A) −/− hESC-derived progenitors and β cells (Zhu et al. Expression of cre recombinase is limited spatially by the promoter, in this case Ptf1a or cpa1(carboxypeptidase 1), and temporally by the addition of a tamoxifen inducible estrogen receptor (ERT) fused to cre. Moreover, in in vivo research, αE‐catenin mutant mice showed impaired islet formation due to increased Sox9 + pancreatic progenitors and enhanced MAPK signaling (Jimenez‐Caliani et al, 2017). It is temporally expressed in tendons during the early stage of development but not in developed tendon cells 17. The pancreas is a mixed exocrine and endocrine gland involved in the control of many homeostatic functions. The FGF10/FGFR2b/SOX9 Elimination of Sox9 in the developing pancreas causes failure to maintain the pool of protodifferentiated precursor cells due to decreased cell proliferation, increased apoptosis, diversion of cells to differentiation to the early endocrine lineage of glucagon-expressing cells , and fate conversion to the liver lineage . Although always reduced compared with wild-type pancreas, the degree of size reduction varied between individual During early pancreatic development, SOX9 plays a pivotal role in controlling pancreatic epithelial progenitor cell proliferation, while in mature pancreas, SOX9 maintains ductal integrity . 1 A, B, F, G). (2012). Recapitulating its effects on pancreatic Sox9 expression, Fgfr abrogation for 72 hours also produced a reduction Here, wereview theserolesof SOX9 in developmental and disease settings and discuss the potential for SOX9 and its modulation as a strategy for diagnosing, predicting and treating disease. Moreover, SOM-null fetuses and pups reduce Sox9 expression by 18–37% in the pancreas, lung, kidney, salivary gland, gut and liver. , 2002; Kawaguchi et al. PMID In view of the defects in mammary development upon Sox9 deletion (discussion above), we suggest that Sox9 is an important regulator of the developmental program of MaSCs. SOX9 During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. At this point the buds contain multiple Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with an extremely poor prognosis. Pancreatic acinar cells can dedifferentiate or transdifferentiate to an embryonic progenitor phenotype that expresses ductal markers, in a process termed acinar-to-ductal metaplasia (ADM) 3. , 2007), raising the question of whether ADM is truly ductal in nature or more closely resembles embryonic We describe a previously unanticipated role for Sox9, a transcriptional regulator of embryonic pancreas and endocrine cell development, in mature beta cells. Cowley, Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia. E. The TFEB-SOX9 axis drives the differentiation status of liver progenitor cells (LPCs) into progenitor/cholangiocyte lineage during liver development and regeneration. 5. Our current studies build on the prior knowledge and show that SOX9+/PTF1A+ cells are found at the tips of the pancreatic The discrepancy between the two models could be explained by differences during early pancreas development. 0, when dorsal and ventral pancreatic buds emerge on opposing sides of the foregut endoderm, fusing by E12. 2, 20, 23,24 Hnf1b-null mice similarly develop a An enhancer region called SOM (activator of SOX9 in somatic tissues), which lies 70 kb upstream of the SOX9 transcription start site, is involved in SOX9 auto-regulation in many somatic tissues during mouse development including the pancreas, lung, kidney, salivary gland, gut and liver (Fig. affected by the Sox9 haploinsufficiency syndrome campomelic dysplasia initially alluded to a functional role of Sox9 in pancreatic morphogenesis, transgenic mouse models have been instrumental in mechanistically Pancreas development represents an example of such a process. 01: Supplemental Figure 1. As the pancreatic buds emerge during embryogenesis, they quickly generate different cell types 2. In mice, such cell fate segregation The use of established differentiation protocols to study the role of GATA6 in pancreas development (Pagliuca et al. It is important to consider that after combined inactivation of Pdx1 and Ptf1a in mice or Xenopus , the dorsal pancreatic bud still forms and early pancreatic KEY WORDS: Sox9, Pancreas, Regeneration, Multipotent progenitor, Neogenesis, Partial duct ligation, Mouse examined the developmental potential of the Sox9+ domain in vivo. On the other hand, pancreas-specific Sox9 depletion in mice resulted in severe pancreas hypoplasia, suggesting that Sox9 functions in the expansion of the pool of multipotent progenitor cells by accelerating their proliferation and survival and by keeping them in an undifferentiated state in early pancreatic development . In three of the four cell lines studied, the transfection of siSOX9 led to a significant We show that pancreatic progenitor-specific ablation of Sox9 during early pancreas development causes pancreas-to-liver cell fate conversion. 3), we found that SOX9 was frequently co-expressed with transcription factors involved in endocrine cell development from 8 to 21 weeks of fetal age. , Pedersen, E. Following patterning, transcription factors, most importantly PDX1, PTF1A, FOXA and SOX9, specify the pancreatic progenitor cells The TFEB-SOX9 axis drives the differentiation status of liver progenitor cells (LPCs) into progenitor/cholangiocyte lineage during liver development and regeneration. There is a second description, similar in overview, in relation to the pancreas as an endocrine organ, see Endocrine - Pancreas Development. Sox9 expression in the pancreatic rudiment was identical to that of Pdx1. , Questions that deserve extensive research include - recruitment of PRCs to specific sites during the course of human pancreas development, effects of post-translational modifications of the Polycomb subunits on cellular transitions, the plasticity Early mouse pancreas development has two characteristic periods: a primary transition Keywords: FGF10, FGFR2b, SOX9, pancreas development, pancreatic adenocarcinoma, mesenchyme, epithelium. Sox9 + ductal cells are multipotent progenitors throughout development but Pancreatic progenitor-specific ablation of Sox9 during early mouse pancreatic development, they report, leads to cell-autonomous loss of fibroblast growth factor receptor 2b (Fgfr2b), which is required to transduce mesenchymal Fgf10 signals. The second possible mechanism of Hippo influence on cell proliferation considers We detected transcripts for Sox11, Sox4, Sox13, Sox5, Sox9, Sox8, Sox10, Sox7, Sox17, Sox18, Sox15, and Sox30 in embryonic pancreas and found Sox4, Sox9, and Sox13 in adult pancreatic islets. In addition, Sox9 + cells are also pancreatic progenitor cells, participating in pancreatic repair reaction induced by injury. D. , 2015). , Questions that deserve extensive research include - recruitment of PRCs to specific sites during the course of human pancreas development, effects of post-translational modifications of the Polycomb subunits on cellular transitions, the plasticity The SOX9 partners that coexpress with SOX9 transcription factor during certain stages of the pancreatic development have been established . Biochem. The transcription factors Sox9, Hnf6 and Hes1 are not only markers for pancreatic ductal cells, but are also expressed in multipotent progenitors of the developing pancreas (Jacquemin et al. (A–D) Individual p-smad2 or p-smad3 staining in CD-1 wild-type pancreas at E15 and E18. One critical component of this fate choice appears to be the level of Neurog3 expression. Development 138 , 653–665 (2011). To trace cells that originate from the embryonic and adult Sox9+ domain, we generated BAC transgenic mice that express Zebrafish and mammalian pancreas consist of endocrine islets embedded in a large exocrine tissue. (2012), Kimmel and Meyer (2010), Villani et al. SOX9, a downstream target of Notch, is expressed from the early stage of pancreatic development and is required for the maintenance of the pancreatic progenitor pool and for establishment of the pancreatic endocrine and exocrine cell fates (15 Sox9 is essential for chondrocyte differentiation and cartilage formation 2. (2000). Pgd2 synthesis Promotes nuclear import of SOX9 [22] Pancreas Activates Ngn3 expression Endocrine specification [31,33] Promotes Hes-1 expression Crosstalk of FGF10 during pancreatic cancer. SOX9, along with SOX10, is essential for gliogenesis in CNS [25, 92, 93]. The FGF10/FGFR2b/SOX9 Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Sox9; Sex-determining region on the Y chromosome related high-mobility group (HMG) box 9; Sur1; Sulfonylurea Receptor 1; Wnt; In this study, Gata6 was inactivated during early pancreas development using the mouse Pdx1-Cre line. 23 At CS13, microluminar Background SOX9, a progenitor cell marker, is important for pancreatic ductal development. Developmental biology of the pancreas Lab; Research output: Contribution to journal › Review › Research › peer-review. GRUBBS,b GIUSEPPE ORLANDO,e ROGER DE FILIPPO,a,f HSUN TERESA KU,c,d,* LAURA PERIN a,f,* Key Words. , 2008). Recently, SOX9 expression, as transcript INTRODUCTION. pancreatic buds, SOX9 was The development of pancreatic cells NA Normal pancreatic tissue scRNA-seq Gregg et al. ca (SOX9) and NK Homeobox 6. However, our work discovered the precise time during pancreas development at which MAPK/ERK regulates endocrine progenitor specification. Our data demonstrate that Sox9 has continued function in beta cells as they mature, and elimination of Sox9 compromises beta cell activities. (c) Microlumens continue to expand during the primary transition, leading to the formation of Keywords: FGF10, FGFR2b, SOX9, pancreas development, pancreatic adenocarcinoma, mesenchyme, epithelium INTRODUCTION The Fibroblast Growth Factor (FGF) family of peptides and the corresponding family of receptor tyrosine kinases (RTKs) collectively constitute one of the most adaptable, complex, and diverse Figure 3. Pancreas development begins at Carnegie stage 10 (CS10) in humans, with the pancreatic bud developing from the foregut region of the endoderm, which is marked by diminishing levels of sonic hedgehog and increasing levels of pancreatic and duodenal homeobox 1 (PDX1). At the foregut/midgut junction the septum transversum generates 2 pancreatic By contrast, Sox9 Δpan/Δpan embryos displayed a reduction of the pancreas to stunted rudiments in both the splenic and duodenal regions, indicating that the development of tissue from both pancreatic buds is abrogated (Fig. , 2005). 5 to form the unified organ. During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. Figure 3: Lineage tracing during pancreatic development. Its role is associated with embryonic development, maintenance of pancreas, hair follicle, CNS, breast, and intestine [[89], [90], [91]]. ZOOK,c,d CHRISTIANA J. NKX6. During zebrafish development, the pdx1 SOX9 is one of the members of SOX E subgroup. The transcription factors Sox9, Hnf6, and Hes1 are not only markers for pancreatic ductal cells, but are also expressed in multipotent progenitors of the developing pancreas (Jacquemin et al. Temporal and spatial expression of SOX9 during human fetal pancreas development Using qRT-PCR, western blotting and immunofluorescent staining, we characterized the temporal expression pattern of SOX9 in the developing human fetal pancreas from 8 to 21 weeks of fetal age. After emerging from the neighboring domains of the foregut endoderm, they turn on distinct differentiation and morphogenesis programs that are regulated by hierarchies of transcription factors. To trace cells that originate from the embryonic and adult Sox9+ domain, we generated BAC transgenic mice that express This section of notes gives an overview of how the pancreas develops as an exocrine organ associated with the gastrointestinal tract. However, as they age (6 months old Additionally, the downregulation of SOX9 expression had a specific effect on the expression of pancreatic developmental master genes. Funder-Nielsen, T. 5 dpc, just before or around the same time as Sry Listed below are a number of pancreatic developmental abnormalities, see also the 2003 article "Lifetime consequences of abnormal fetal pancreatic development". Our current studies build on the prior knowledge and show that SOX9+/PTF1A+ cells are found at the tips of the pancreatic nisms controlling embryonic pancreas development has significantly advanced. Key transcription factors of the pancreatic organogenesis (adapted from [ 29 ]) The plethora of signaling pathways involved in pancreas development is activated in a highly coordinated manner to assure unmitigated development and morphogenesis in vertebrates. The constitutively active ROSA26 drives We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into beta cells in mice with reversal of Loss of Sox9 during pancreas development results in pancreas hypoplasia, whereas inactivation in adults sensitizes duct cells to dysplasia. Low caNotch activity promotes the tip cell fate, which later generates acinar cells. Following gastrulation, 2 patches of endoderm (yellow)—1 in the ventral foregut and 1 in the dorsal midgut—receive signals from adjacent structures resulting in During human development, all adult pancreatic cells originate from the same multipotent pancreatic progenitor cells (MPCs) that express a group of transcription factors (TFs), including PDX1, SOX9, FOXA2, NKX6. , 2013). Previous. The positive feedback loops between FGF10-SOX9, KRAS/NF-κB-SOX9, and ERBB-SOX9, respectively, are enhanced under inflammatory condition, which contributes to PDAC initiation and progression. Int. (b) Microlumens form; apical polarity established (red outline in b, and c). Here, the authors show that loss of Sox9 in mature beta cells The pancreas is a glandular organ with two main types of cells: endocrine islet cells, which produce hormones to regulate metabolism and glucose levels, and exocrine acinar and The mature pancreas performs two distinct functions: acinar cells of the exocrine pancreas secrete digestive enzymes, which are transported to the duodenum through ducts While pancreatic cancer remains one of the toughest cancers to treat and is predicted to become the second-leading cause of cancer-related death in the U. To define the Notch signaling niche during the major time period of pancreatic endocrine differentiation, we performed co-immunofluorescence analysis for Notch receptors together with known Notch downstream effectors, Rbpj and Hes1, as well as Sox9 and Ngn3. Knowledge of human pancreas development underpins our interpretation and exploitation of human pluripotent stem cell (PSC) differentiation towards a β-cell fate. Their development share many key steps and players (Kinkel and Prince, 2009 for review). Grimont, A. Development, 138(4):653-665. , 2007), raising the question of whether ADM is truly ductal in nature or more closely resembles embryonic Pancreas development in vertebrates is an intricate process through which various cell lineages develop from common endodermal progenitors and converge to form a single organ [3, 4]. Similar to Sox9, expression patterns of Sox4 are broad across pancreatic buds in early pancreatic development and restricted to the endocrine cells of the islets by adulthood (57, 104). Interestingly, observations regarding functional effects of Sox4 have been very similar to those made for Sox9. Ptf1a initially functions as the pancreatic-determinant gene during the fate separation of the When pancreas development or islet cell functions go awry, due to mutation in genes important for proper organogenesis and development, the result can lead to a common pancreatic affliction, diabetes mellitus. During early pancreas development, PDX1 is expressed throughout the epithelium, diminishes in midgestation Our results strongly support a dynamic expression of HNF1β and SOX9 in pancreatic duct cells that may reflect the state of differentiation of the duct cells. 2000; Our results strongly support a dynamic expression of HNF1β and SOX9 in pancreatic duct cells that may reflect the state of differentiation of the duct cells Pancreas development represents an example of such a process. Pancreas † Because the dedifferentiated cells exhibit qualities reminiscent of both a duct cell and a progenitor cell present during pancreatic development (including the expression of Sox9, Hnf6, Hes1, Pdx1, and Nestin), the term duct-like cell has been used to describe this population (Song et al. Here they show that loss of NEUROD1 leads to disturbances in endocrine cell SOX9 is required for the development of the biliary system 45 , and the pancreas [46][47][48] , and for acinar to ductal metaplasia during pancreatic cancer development 19 . Therefore, pancreas-specific Sox9 ablation leads to hypoplasia of the gland . However, the role of PTF1A in the hFP has been elusive. Dorsal (dp) and ventral (vp) pancreatic buds can be visualized (yellow) along with the stomach (sto), duodenum (duo), and liver bud (Li) in the posterior foregut at e10. pancreatic buds, SOX9 was SOX9, a downstream target of Notch, is expressed from the early stage of pancreatic development and is required for the maintenance of the pancreatic progenitor pool and for establishment of the pancreatic endocrine and exocrine cell fates [15], [17]. multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. 37 In addition, SOX9 is acknowledged as a ductal cell maker Sox9 + cells in the developing pancreas are Notch responsive. 1 + cells to generate ducts and Neurog3 + endocrine progenitors. These cells are responsible for the formation Early Steps during Embryonic Pancreas Development. In humans, SOX9 haploinsufficiency leads to campomelic dysplasia with pancreatic dysmorphogenesis []. At this stage, SOX9 expression was barely perceptible either in the developing vertebral body or Overview of pancreas development. , 2002; Akiyama et al. (A–D) Efficacy of smad2 and smad3 morpholino treatment in E11. B, FOS and FOSL1 immunostaining in the pancreas of Control Sox9 mice and in Our results strongly support a dynamic expression of HNF1b and SOX9 in pancreatic duct cells that may reflect the state of differentiation of the duct cells. has a crucial role in epithelial branching morphogenesis through crosstalk with several key TFs and regulators for pancreas development. STZ is commonly used to induce pancreatic β cell injury. The constitutively active ROSA26 drives Of the adult cell lineages of the pancreas, acinar cells show the highest plasticity 1,2. These include 1) 'endocrine pancreas development', consistent with the known function of SOX9 activity in the pancreas during embryogenesis (9,49, 52) and 2) 'stem-cell maintenance', reflecting Sox9 regulates alternative splicing and pancreatic beta cell function. 1 + Hnf1bdomain marks the distal ends of the embryonic cords of mouse pancreas. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. SOX9 expression was evaluated by immunohistochemistry in 146 benign pancreas (BP), 136 pancreatic ductal adenocarcinomas, 47 pancreatic development (14, 17, 22, 23). SOX9 In normal pancreas, SOX9 maintains the progenitor pool for multiple pancreatic cells, including exocrine and endocrine cells. , 2014, Rezania et al. , Lindsell, C. Embryonic pancreatic Sox9-expressing cells Key pancreatic factors Sox9 and Ptf1a do not interact with Swi/Snf complexes (Spaeth et al. Pdx1 and Sox9, as The transcription factors Sox9, Hnf6, and Hes1 are not only markers for pancreatic ductal cells, but are also expressed in multipotent progenitors of the developing pancreas (Jacquemin et al. Expression of Fgfr2b is During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. 1 Therefore, earlier diagnosis and more effective therapies are required to improve outcomes, which require a better understanding of the molecular mechanisms of PDAC development. (E) QPCR ontogeny for smad4 at different embryonic stages of development (+/− S. . (A-A) Immunofluorescence staining reveals that the Sox9 + and Hnf1b + domains largely coincide As development proceeds, Sox9 expression can be used to trace the development of the dorsal and ventral pancreatic buds and their repositioning associated with the dynamic movements of the gastrointestinal tract. SOX9 expression is In addition to maintaining both multipotent and bipotent pancreatic progenitors, Sox9 is also required for initiating endocrine differentiation and maintaining pancreatic ductal identity, and it We present here a detailed fate analysis of the pancreatic Sox9 + domain during embryonic development, adulthood and in response to pancreatic injury by PDL. Classical features of this disorder (e. Duct cells in adult mice are quiescent for the most part, with only 2% of Sox4 in Pancreatic Development. 86 Additionally, the NF-κB subunit p65 positively regulates SOX9 expression by directly binding to the Sox9 promoter, which may influence the subsequent invasiveness of The spatial and temporal expression pattern of SOX9 during human pancreas development was dissected, with an emphasis on its role in islet cell differentiation 53. Development of the Pancreas Christopher Pin and Melissa Fenech University of Western Ontario, London Ontario e-mail: cpin@uwo. , 2016), although it is known to be crucial from the earlier stages of human pancreas development, since mutations in PTF1A coding or regulatory sequences lead to pancreas agenesis and Errors during pancreas development and specification of the endocrine lineage can result in severe neonatal diabetes. skeletal dysplasia and 46,XY sex reversal) are in concordance with SOX9 expression profiles during human embryonic development. 1 b) (Mead et al. For example, they form as two embryonic buds from the pdx1-expressing domain of the endoderm adjacent to the hepatic primordium. V. Methods SOX9 expression was evaluated by immunohistochemistry SOX9+/PTF1A+ Cells Define the Tip Progenitor Cells of the Human Fetal Pancreas of the Second Trimester VALENTINA VILLANI,a MATTHEW E. vshx flojc ydlbuyb kpsc uvhiw kvwvdu kdxat wtpet tdm irufwgh