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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KrasG12D and Smad4/Dpc4 Haploinsufficiency Cooperate to Induce Mucinous Cystic Neoplasms and Invasive Adenocarcinoma of the Pancreas
Kamel Izeradjene,Chelsea Combs,Melissa Best,Aarthi Gopinathan,Amary Wagner,William M. Grady,William M. Grady,Chu-Xia Deng,Ralph H. Hruban,N. Volkan Adsay,David A. Tuveson,Sunil R. Hingorani,Sunil R. Hingorani +12 more
TL;DR: In this article, the authors show that concomitant expression of Kras(G12D) and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous cystic neoplasms (MCNs), which culminate in invasive ductal adenocarcinomas.
Journal ArticleDOI
On the origin of the β cell
TL;DR: A review of the current knowledge of these factors as they relate specifically to the emergence of endocrine β cells from pancreatic endoderm is provided in this article, where the authors describe the current state-of-the-art in this area.
Journal ArticleDOI
Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma
Pawel K. Mazur,Alexander Herner,Stephano S. Mello,Matthias Wirth,Simone Hausmann,Francisco J. Sánchez-Rivera,Shane Lofgren,Timo Kuschma,Stephan A. Hahn,Deepak Vangala,Marija Trajkovic-Arsic,Aayush Gupta,Irina Heid,Peter B. Noël,Rickmer Braren,Mert Erkan,Jörg Kleeff,Bence Sipos,Leanne C. Sayles,Mathias Heikenwalder,Mathias Heikenwalder,Elisabeth Heßmann,Volker Ellenrieder,Irene Esposito,Tyler Jacks,James E. Bradner,Purvesh Khatri,E. Alejandro Sweet-Cordero,Laura D. Attardi,Roland M Schmid,Roland M Schmid,Guenter Schneider,Julien Sage,Jens T. Siveke,Jens T. Siveke +34 more
TL;DR: The studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors by using a CRISPR-Cas9–based method for gene editing directly in the mouse adult pancreas.
Journal ArticleDOI
Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma
Weiying Zhang,Nivedita Nandakumar,Yuhao Shi,Mark Manzano,Alias Smith,Garrett T. Graham,Swati Gupta,Eveline E. Vietsch,Sean Z. Laughlin,Mandheer Wadhwa,Mahandranauth A. Chetram,Mrinmayi Joshi,Fen Wang,Bhaskar Kallakury,Jeffrey A. Toretsky,Anton Wellstein,Chunling Yi +16 more
TL;DR: Yap acted as a critical transcriptional switch downstream of the oncogenic KRAS–mitogen-activated protein kinase (MAPK) pathway, promoting the expression of genes encoding secretory factors that cumulatively sustained neoplastic proliferation, a tumorigenic stromal response in the tumor microenvironment, and PDAC progression in Kras and Kras:Trp53 mutant pancreas tissue.
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.