Journal ArticleDOI
The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors
Yoshiya Kawaguchi,Bonnie Cooper,Maureen Gannon,Michael Ray,Raymond J. MacDonald,Christopher V.E. Wright +5 more
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TLDR
Rec recombination-based lineage tracing in vivo is used to show that PTF1a is expressed at these early stages in the progenitors of pancreatic ducts, exocrine and endocrine cells, rather than being an exocrine-specific gene as previously described.Abstract:
Pancreas development begins with the formation of buds at specific sites in the embryonic foregut endoderm. We used recombination-based lineage tracing in vivo to show that Ptf1a (also known as PTF1-p48) is expressed at these early stages in the progenitors of pancreatic ducts, exocrine and endocrine cells, rather than being an exocrine-specific gene as previously described. Moreover, inactivation of Ptf1a switches the character of pancreatic progenitors such that their progeny proliferate in and adopt the normal fates of duodenal epithelium, including its stem-cell compartment. Consistent with the proposal that Ptf1a supports the specification of precursors of all three pancreatic cell types, transgene-based expression of Pdx1, a gene essential to pancreas formation, from Ptf1a cis-regulatory sequences restores pancreas tissue to Pdx1-null mice that otherwise lack mature exocrine and endocrine cells because of an early arrest in organogenesis. These experiments provide evidence that Ptf1a expression is specifically connected to the acquisition of pancreatic fate by undifferentiated foregut endoderm.read more
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The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis
Motoyuki Tsuda,Akihisa Fukuda,Nilotpal Roy,Yukiko Hiramatsu,Laura Leonhardt,Nobuyuki Kakiuchi,Kaja Hoyer,Satoshi Ogawa,Norihiro Goto,Kozo Ikuta,Yoshito Kimura,Yoshihide Matsumoto,Y. Takada,Takuto Yoshioka,Takahisa Maruno,Yuichi Yamaga,Grace E. Kim,Haruhiko Akiyama,Seishi Ogawa,Christopher V.E. Wright,Dieter Saur,Kyoichi Takaori,Shinji Uemoto,Matthias Hebrok,Tsutomu Chiba,Hiroshi Seno +25 more
TL;DR: The BRG1/SOX9 axis is a potential target for PanIN-derived PDA after exclusive elimination of BrG1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p 53 mutation.
Journal ArticleDOI
Cell autonomy of DSCAM function in retinal development
TL;DR: Dscam dosage-dependent defects in developmental cell death and amacrine cell spacing are found, relevant to the increased cell death in Down syndrome mouse models and human patients, in which Dscam is present in three copies.
Journal ArticleDOI
Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells.
TL;DR: The findings identify Mnx1 as an important factor in β-cell differentiation and proliferation, with the potential for targeting to increase the number of endogenous β-cells for diabetes therapy, and a role in compensatory beta-cell proliferation.
Journal ArticleDOI
ETS‐family genes in pancreatic development
TL;DR: It is found that two members of the Etv subfamily, Etv4 and Etv5, are expressed in cells proximal to pancreatic mesenchyme, and induced in FGF10‐arrested pancreatic progenitors suggesting that these factors mediate mesenchymal‐to‐epithelial signaling.
Journal ArticleDOI
Erlotinib Prolongs Survival in Pancreatic Cancer by Blocking Gemcitabine-Induced MAPK Signals
Koji Miyabayashi,Hideaki Ijichi,Dai Mohri,Motohisa Tada,Keisuke Yamamoto,Yoshinari Asaoka,Tsuneo Ikenoue,Keisuke Tateishi,Yousuke Nakai,Hiroyuki Isayama,Yasuyuki Morishita,Masao Omata,Harold L. Moses,Kazuhiko Koike +13 more
TL;DR: The combination of gemcitabine and erlotinib is superior to gemcitABine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout), and a significant role of ERBB is suggested in PDAC treatment.
References
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Journal ArticleDOI
Insulin-promoter-factor 1 is required for pancreas development in mice
TL;DR: The findings show that IPF1 is needed for the formation of the pancreas and suggest that it acts to determine the fate of common pancreatic precursor cells and/ or to regulate their propagation.
Journal ArticleDOI
Differentiation of Embryonic Stem Cells to Insulin-Secreting Structures Similar to Pancreatic Islets
Nadya Lumelsky,Olivier Blondel,Olivier Blondel,Pascal Laeng,Iván Velasco,Rea Ravin,Ronald D.G. McKay +6 more
TL;DR: This work generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells that self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons.
Journal ArticleDOI
PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum
Martin F. Offield,T. L. Jetton,Patricia A. Labosky,Michael Ray,Roland Stein,Mark A. Magnuson,Brigid L.M. Hogan,Christopher V.E. Wright +7 more
TL;DR: The pdx-1/beta-galactosidase fusion allele is expressed in pancreatic and duodenal cells in the absence of functional PDX-1, with expression continuing into perinatal stages with similar boundaries and expression levels, and offers additional insight into the role of p dx-1 in the determination and differentiation of the posterior foregut.
Journal ArticleDOI
Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors.
TL;DR: The results provide direct evidence that NGN3+ cells are islet progenitors during embryogenesis and in adult mice, and suggest that lineages for exocrine, endocrine islet and duct progenitor are committed at mid-gestation.