Conversion of biliary system to pancreatic tissue in Hes1-deficient mice

Sumazaki, Ryo; Shiojiri, Nobuyoshi; Isoyama, Shigemi; Masu, Masayuki; Keino‐Masu, Kazuko; Osawa, Mitsujiro; Nakauchi, Hiromitsu; Kageyama, Ryoichiro; Matsui, Akira

doi:10.1038/ng1273

Cited by 221 publications

(188 citation statements)

References 28 publications

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“…Indeed, it has even been shown that endocrine clusters, including b-cells, occur naturally in the extrahepatic bile ducts of adult mice (Dutton et al, 2007). The plasticity of the early foregut endoderm is further demonstrated in global Hes1-deficient mice, where significant amounts of ectopic pancreatic tissue containing islets and acini were closely associated with the common bile duct (Sumazaki et al, 2004;Fukuda et al, 2006).…”

Section: Exocrine Cell Development Ducts and Centroacinar Cellsmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

528

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Section: Exocrine Cell Development Ducts and Centroacinar Cellsmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

528

594

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“…Hes1 maintains progenitors by inhibiting the expression of these bHLH activators. Genetic inactivation of Hes1 up-regulates the expression of these bHLH activators, resulting in, for example, severe pancreatic hypoplasia and the formation of an ectopic pancreas (Fukuda et al, 2006;Jensen et al, 2000;Sumazaki et al, 2004). Hes1 is also expressed in the intestinal crypt, where stem cells and proliferating progenitors are located, and represses the expression of bHLH-type activator genes, Math1 and Ngn3, whose translational products promote the differentiation of secretory cells.…”

Section: Roles Of Hes Factors In Various Tissuesmentioning

confidence: 99%

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Kobayashi

Kageyama

2014

Current Topics in Developmental Biology

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Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1 to Hes7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences while the HLH region forms homo-and hetero-dimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits co-repressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate determination steps of embryonic stem cells and neural progenitor cells. Here we discuss some key features of Hes factors in development and diseases.

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“…Hes1 operates as a general negative regulator of endodermal endocrine differentiation, and defects in Notch signaling lead to accelerated pancreatic endocrine differentiation. 3 Hes1 is expressed in the extrahepatic biliary epithelium throughout development. In Hes1 knock-out mice, biliary epithelium ectopically expresses the proendocrine gene Neurog3, differentiates into pancreatic endocrine and exocrine cells and forms acini and islet-like structures in the mutant bile ducts, followed by the conversion of much of the extrahepatic biliary primordium to ectopic pancreas.…”

Section: The Biliary Tract Has Bipotential Differentiationmentioning

confidence: 99%

“…[3][4][5] Expression of Hes1 is controlled by the evolutionarily conserved Notch pathway. Hes1 operates as a general negative regulator of endodermal endocrine differentiation, and defects in Notch signaling lead to accelerated pancreatic endocrine differentiation.…”

Section: The Biliary Tract Has Bipotential Differentiationmentioning

confidence: 99%

“…Both organs derive from the foregut at almost the same time, and recent studies using animals have revealed that they show plasticity to each other during development. 2 Furthermore, studies with genetically altered animals showed that the biliary tract shows pancreatic differentiation, [3][4][5] though this is prevented physiologically in humans. Diseases of the biliary tract and pancreas have a similar pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

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A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: Is the biliary tract an incomplete pancreas?

Nakanuma¹

2010

Pathology International

153

130

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There are peribiliary glands around the biliary tract, and these glands drain into the bile duct lumen. Interestingly, small amounts of pancreatic exocrine acini are intermingled with these glands. Experimental studies using animals suggest that the biliary tract shows some potential for pancreatic differentiation. It is noteworth that the biliary tract and pancreas have similar pathological features. IgG4-related sclerosing cholangitis and autoimmune pancreatitis are representative inflammatory diseases with similar features. Intraductal papillary neoplasms are found in the biliary tract and also in the pancreas: intraductal papillary neoplasm of the bile duct (IPNB) and intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNB and IPMN share common histologic and phenotypic features and biological behaviors. Interestingly, mucinous cystic neoplasm (MCN) arises in both the pancreas and the heaptobiliary system. Intraductal tubular neoplasia is found in both the biliary tract and pancreas as well. Intraepithelial neoplasm is found in the biliary tract and pancreas: biliary intraepithelial neoplasm (BilIN) and pancreatic intraepithelial neoplasm (PanIN). BilIN and PanIN are followed by conventional invasive adenocarcinoma, while IPNB and IPMN are followed by tubular adenocarcinoma and mucinous carcinoma in both organs. Further study of the biliary tract's pathophysiology based on its similarity to pancreatic counterparts is warranted.

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Conversion of biliary system to pancreatic tissue in Hes1-deficient mice

Abstract: The biliary system, pancreas and liver all develop from the nearby foregut at almost the same time in mammals. The molecular mechanisms that determine the identity of each organ in this complex area are unknown.

Cited by 221 publications

References 28 publications

Pancreas organogenesis: From bud to plexus to gland

Pancreas organogenesis: From bud to plexus to gland

Expression Dynamics and Functions of Hes Factors in Development and Diseases

A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: Is the biliary tract an incomplete pancreas?

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