Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas

Fujikura, Junji; Hosoda, Kiminori; Iwakura, Hiroshi; Tomita, Tsutomu; Noguchi, Michio; Masuzaki, Hiroaki; Tanigaki, Kenji; Yabe, Daisuke; Honjo, Tasuku; Nakao, Kazuwa

doi:10.1016/j.cmet.2005.12.005

Cited by 105 publications

(96 citation statements)

References 33 publications

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“…These include Notch1-4, Deltalike 1 (Dll1), Dll3, Jagged1, Jagged2, Serrate1, and Serrate2 (Lammert et al, 2000;Jensen et al, 2000b). Mice deficient for various Notch pathway components, such as RBPJ, Dll1, and Hes1, display pancreatic hypoplasia resulting from precocious endocrine differentiation that causes progenitor pool depletion (Apelqvist et al, 1999;Jensen et al, 2000b;Fujikura et al, 2006). Furthermore, overexpressing Notch3 ICD , which represses Notch1-mediated upregulation of Hes1 in vivo, also results in reduced pancreas size and epithelial branching, with concurrent accelerated endocrine differentiation (Apelqvist et al, 1999).…”

Section: Notch Signaling In Early Pancreatic Progenitor Developmentmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

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: Notch Signaling In Early Pancreatic Progenitor Developmentmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

594

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“…This appears to be due to caNotch signaling because similar phenotypes involving pancreatic growth arrest are observed with genetic mouse models deficient in recombining binding protein suppressor of hairless (RBPJ-k), a transcriptional mediator of caNotch signaling (14) or Hes1 (24,35,46,49). Apart from Hes1, Notch signaling also regulates Sox9, a transcription factor that, like Hes1, has multiple developmental roles in many tissues (2,46,(50)(51)(52)(53)(54).…”

Section: Overview Of Pancreas Development and Involvement Of Key Pathmentioning

confidence: 99%

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

et al. 2016

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Loss of insulin-producing pancreatic islet β-cells is a hallmark of type 1 diabetes. Several experimental paradigms demonstrate that these cells can, in principle, be regenerated from multiple endogenous sources using signaling pathways that are also used during pancreas development. A thorough understanding of these pathways will provide improved opportunities for therapeutic intervention. It is now appreciated that signaling pathways should not be seen as “on” or “off” but that the degree of activity may result in wildly different cellular outcomes. In addition to the degree of operation of a signaling pathway, noncanonical branches also play important roles. Thus, a pathway, once considered as “off” or “low” may actually be highly operational but may be using noncanonical branches. Such branches are only now revealing themselves as new tools to assay them are being generated. A formidable source of noncanonical signal transduction concepts is neural stem cells because these cells appear to have acquired unusual signaling interpretations to allow them to maintain their unique dual properties (self-renewal and multipotency). We discuss how such findings from the neural field can provide a blueprint for the identification of new molecular mechanisms regulating pancreatic biology, with a focus on Notch, Hes/Hey, and hedgehog pathways.

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“…Exons 6 and 7 encode DNA-binding and Notch-binding domains, and the lack of these exons results in the complete loss of Rbp-j-mediated Notch signaling. Rbp-j f is a very efficient target for Cre recombinase in multiple tissues Tanigaki et al, 2002Tanigaki et al, , 2004Yamamoto et al, 2003;Fujikura et al, 2006;Buono et al, 2006). Recently, we reported the generation of mice in which the Rbp-j gene was inactivated by Cre recombinase under the control of the Pdx1 promoter (Rbp-j f/f Pdx.cre; Fujikura et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…However, multiple anomalies and early embryonic deaths of mice with homozygous deletions of such genes limit the possible assessment of the importance of Notch signaling in this organ (Swiatek et al, 1994;Ishibashi et al, 1995;Oka et al, 1995;Hrabé de Angelis et al, 1997;Xue et al, 1999;Apelqvist et al, 1999;Hamada et al, 1999;Jensen et al, 2000). We recently reported the generation of mice in which the Rbp-j gene is inactivated by Cre recombinase under the control of the Pdx1 promoter (Rbp-j f/f Pdx.cre mice; Fujikura et al, 2006). Pdx1 is a homeobox transcription factor required for pancreatic outgrowth and the differentiation of the rostral duodenum (Offield et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Rbp‐j regulates expansion of pancreatic epithelial cells and their differentiation into exocrine cells during mouse development

Fujikura

Hosoda

Kawaguchi

et al. 2007

Developmental Dynamics

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Notch signaling regulates cell fate determination in various tissues. We have reported the generation of mice with a pancreas-specific knockout of Rbp-j using Pdx.cre mice. Those mice exhibited premature endocrine and ductal differentiation. We now generated mice in which the Rbp-j gene was inactivated in Ptf1a-expressing cells using Ptf1a.cre mice. The timing of the Cre-mediated deletion in Rbp-j f/f Ptf1a.cre mice is 1 day later than that in Rbp-j f/f Pdx.cre mice. In Rbp-j f/f Ptf1a.cre mouse pancreases, at E13.5, the reduced Hes1 expression was accompanied by reduced epithelial growth, but premature endocrine cell differentiation was minimal. At E15.5, Pdx1 expression was repressed and acinar cell differentiation was reduced, but an increase in acinar cell proliferation was observed during the perinatal period. Our study indicates that, in addition to its role in preventing premature differentiation of early endocrine cells, Rbp-j regulates epithelial growth, Pdx1 expression, and acinar cell differentiation during mid-pancreatic development. Developmental Dynamics 236:2779 -2791, 2007.

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Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas

Cited by 105 publications

References 33 publications

Pancreas organogenesis: From bud to plexus to gland

Pancreas organogenesis: From bud to plexus to gland

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

Rbp‐j regulates expansion of pancreatic epithelial cells and their differentiation into exocrine cells during mouse development

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