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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Forgotten and novel aspects in pancreas development.
Tomas Pieler,Yonglong Chen +1 more
TL;DR: Evolutionary aspects of pancreas development are addressed, emphasizing the role of the South African clawed frog, Xenopus laevis, as an additional useful model system to study the molecular control of pancreatic development.
Journal ArticleDOI
PanIN-Specific Regulation of Wnt Signaling by HIF2α during Early Pancreatic Tumorigenesis
Angela Criscimanna,Li-Juan Duan,Julie Rhodes,Volker Fendrich,Emily Diane Wickline,Douglas J. Hartman,Satdarshan P.S. Monga,Michael T. Lotze,George K. Gittes,Guo-Hua Fong,Farzad Esni +10 more
TL;DR: It is shown that Hif2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer, and with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and β-catenin.
Journal ArticleDOI
SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy
Zhentian Wang,Simone Hausmann,Ruitu Lyu,Tie-Mei Li,Shane Lofgren,Natasha M. Flores,Mary Esmeralda Fuentes,Marcello Caporicci,Ze Yang,Matthew J. Meiners,Marcus A. Cheek,Sarah A. Howard,Lichao Zhang,Joshua E. Elias,Michael P. Kim,Anirban Maitra,Huamin Wang,Michael C. Bassik,Michael-Christopher Keogh,Julien Sage,Or Gozani,Pawel K. Mazur +21 more
TL;DR: This work identifies SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi) and suggests a context for advancing MEKi use in the clinic.
Journal ArticleDOI
GABA and synaptic inhibition of mouse cerebellum lacking glutamate decarboxylase 67.
Kunihiko Obata,Moritoshi Hirono,Nobuko Kume,Yoshiya Kawaguchi,Shigeyoshi Itohara,Yuchio Yanagawa +5 more
TL;DR: In this study, selective GAD67 deletion was achieved using a Cre-loxP strategy and GABA level was reduced to 16-44% in the Cerebellum but not in the cerebrum, suggesting that GABA does not participate in cerebellar development substantially.
Journal ArticleDOI
Cathepsin D regulates cathepsin B activation and disease severity predominantly in inflammatory cells during experimental pancreatitis.
Ali A. Aghdassi,Daniel S. John,Matthias Sendler,F. Ulrich Weiss,Thomas Reinheckel,Julia Mayerle,Markus M. Lerch +6 more
TL;DR: CTSD is expressed in pancreatic acinar and inflammatory cells, undergoes subcellular redistribution and activation during experimental pancreatitis, and regulates disease severity by potently activating CTSB.
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.