The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors
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.
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Specific recombination in epithelial cells of the pancreas was confirmed by immunohistochemical stainings for tdRFP.
“Specific recombination in epithelial cells of the pancreas was confirmed by immunohistochemical stainings for tdRFP in Ptf1aCre/+ [35] x LSL-tdRFPKI/KI [55, 56] mice (Additional file 1: Fig. S3d) [56].”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [35]
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“, 2001) and P48 mice (Kawaguchi et al., 2002) were previously described.”
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DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., et al. (2011) · Nature · doi:10.1038/nature10189 · Cited by 2,277 · see citing works
“Methods Summary Mouse strains were described previousl”
BackgroundOncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
“These mice were crossed to ROSA26-LSL-rtTA-IRES-GFP (ROSA_rtTA) (Belteki et al., 2005) and p48-Cre (Kawaguchi et al., 2002) mice to enable pancreas-specific and doxycycline (doxy)-inducible expression of KrasG12D (Figure S1B).”
Guerra, C., Schuhmacher, A. J., Cañamero, M., Grippo, P. J., Verdaguer, L., Pérez-Gallego, L., Dubus, P., Sandgren, E. P., & Barbacid, M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.012 · Cited by 1,224 · see citing works
“, 2001) is turned on during the early stages of embryonic pancreatic development by expressing a Cre recombinase under the control of the Pdx1 or P48 promoters (Kawaguchi et al., 2002; Kim and MacDonald, 2002).”
BackgroundAguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J., Redston, M. S., & DePinho, R. A. (2003) · Genes & Development · doi:10.1101/gad.1158703 · Cited by 1,033 · see citing works
“…an extensive independent study by Tuveson and colleagues of mice harboring LSL-KrasG12D and either a different Pdx1-Cre allele or a p48-Cre allele (Kawaguchi et al. 2002; S.R. Hingorani, E.F. Petricoin, A. Maitra, V. Rajapaske, C. King, M.A. Jacobetz, B.A. Hitt, Y. Kawaguchi, L.A. Liotta, H.C.…”
BackgroundModelling human development and disease in pluripotent stem-cell-derived gastric organoids
McCracken, K. W., Catá, E. M., Crawford, C. M., Sinagoga, K. L., Schumacher, M., Rockich, B. E., Tsai, Y.-H., Mayhew, C. N., Spence, J. R., Zavros, Y., et al. (2014) · Nature · doi:10.1038/nature13863 · Cited by 980 · see citing works
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“For developing organs, whole mount X-gal staining was performed as described previousl”
Self-citationOncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
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“Animal Models The LSL-Kras and p48-Cre strains have been described previously (Jackson et al., 2001; Kawaguchi et al., 2002).”
BackgroundMaximizing mouse cancer models
Frese, K. K., & Tuveson, D. A. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2192 · Cited by 711 · see citing works
The Hes gene family: repressors and oscillators that orchestrate embryogenesis
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“4A) (Krapp et al., 1998; Gradwohl et al., 2000; Kawaguchi et al., 2002).”
Bardeesy, N., Cheng, K.-H., Berger, J. H., Chu, G. C., Pahler, J., Olson, P., Hezel, A. F., Horner, J., Lauwers, G. Y., Hanahan, D., et al. (2006) · Genes & Development · doi:10.1101/gad.1478706 · Cited by 674 · see citing works
“We crossed Smad4lox homozygous mice to either the Pdx1-Cre or Ptf1a-Cre transgenic mice (Gu et al. 2002; Kawaguchi et al. 2002) (hereafter, for brevity, Cre will be used for references to both strains together); these transgenes direct Cre recombinase expression to the epithelial lineages of the embryonic pancreas (Pd…”
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Pan, F. C., & Wright, C. (2011) · Developmental Dynamics · doi:10.1002/dvdy.22584 · Cited by 638 · see citing works
“‘‘Global deletion’’ of Pdx1 or Ptf1a in the early foregut epithelium blocks pancreas development and subsequently allows only large cystic ducts to form (Offield et al., 1996; Kawaguchi et al., 2002).”
BackgroundResultInfluentialSelf-citationThe role of TGF-β/SMAD4 signaling in cancer
Zhao, M., Mishra, L., & Deng, C.-X. (2018) · International Journal of Biological Sciences · doi:10.7150/ijbs.23230 · Cited by 631 · see citing works
“Although knockout of SMAD4 by pancreatic-specific PDX1-Cre or P48-Cre did not initiate pancreatic cancer in mice [63, 64], they markedly facilitated tumor progression initiated by KRASG12D activation [65] or PTEN inactivation [66].”
BackgroundGeneration and Regeneration of Cells of the Liver and Pancreas
Zaret, K., & Grompe, M. (2008) · Science · doi:10.1126/science.1161431 · Cited by 601 · see citing works
A Multipotent Progenitor Domain Guides Pancreatic Organogenesis
Zhou, Q., Law, A. C., Rajagopal, J., Anderson, W. J., Gray, P. A., & Melton, D. A. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.06.001 · Cited by 530 · see citing works
“Cells in the nascent pancreatic buds have a similar epithelial morphology and stain broadly for Pdx1 and Ptf1a , two transcription factors (TFs) required for pancreas development (Jonsson et al., 1994; Kawaguchi et al., 2002; Offield et al., 1996).”
BackgroundChurchill, A., Gutiérrez, G. D., Singer, R. A., Lorberbaum, D. S., Fischer, K. A., & Sussel, L. (2017) · eLife · doi:10.7554/elife.20010 · Cited by 543 · see citing works
“…1 (Pdx1) and Pancreas transcription factor 1a (Ptf1a), transcriptional regulators that are essential for pancreatic formation; deletion of Pdx1 or Ptf1a leads to pancreatic agenesis (Burlison et al., 2008; Gu et al., 2003; Jonsson et al., 1994; Kawaguchi et al., 2002; Offield et al., 1996).”
BackgroundGeneration of Insulin‐Producing Islet‐Like Clusters from Human Embryonic Stem Cells
Jiang, J.-J., Au, M., Lu, K., Eshpeter, A., Korbutt, G., Fisk, G. J., & Majumdar, A. (2007) · Stem Cells · doi:10.1634/stemcells.2006-0761 · Cited by 534 · see citing works
Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression
Fukuda, A., Wang, S. C., Morris, J. P., Folias, A. E., Liou, A., Kim, G. E., Akira, S., Boucher, K., Firpo, M., Mulvihill, S., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.002 · Cited by 531 · see citing works
“…we examined Stat3 signaling during pancreatitis-induced PanIN development in mice expressing a conditional, constitutively active form of Kras (KrasG12D) (Hingorani et al., 2003) targeted to pancreatic progenitors under the control of the Ptf1a promoter (Ptf1a-Cre) (Kawaguchi et al., 2002).”
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Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527 · see citing works
“The Pdx1 and Ptf1-p48 promoters are active in the common progenitors of all pancreatic cell types with relatively restricted expression outside of the pancreas (Pdx1 is also expressed in the developing duodenum and stomach, and Ptf1-p48 is expressed in the cerebellum) (Kawaguchi et al. 2002; Gu et al. 2003).”
EGF Receptor is Required for KRAS-induced Pancreatic Tumorigenesis
Ardito, C. M., Grüner, B., Takeuchi, K. K., Lubeseder-Martellato, C., Teichmann, N., Mazur, P., DelGiorno, K. E., Carpenter, E. S., Halbrook, C., Hall, J. C., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.07.024 · Cited by 522 · see citing works
“Mice KrasLSL-G12D/+, Ptf1aCre/+, Ela-Tgfa, Trp53fl/fl, Adam17DEx5/DEx5, and Egfrfl/fl strains have been described elsewhere (Hingorani et al., 2003; Kawaguchi et al., 2002; Lee and Threadgill, 2009; Marino et al., 2000; Natarajan et al., 2007; Sandgren et al., 1990; Siveke et al., 2007; Tang et…”
BackgroundSolar, M., Cardalda, C., Houbracken, I., Martín, M., Maestro, M., Demedts, N., Xu, X.-B., Grau, V., Heimberg, H., Bouwens, L., et al. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.11.003 · Cited by 516 · see citing works
“5 (Herrera, 2000; Kawaguchi et al., 2002; Gu et al., 2002).”
Stromal response to Hedgehog signaling restrains pancreatic cancer progression
Lee, J. J., Perera, R. M., Wang, H., Wu, D.-C., Liu, X. S., Han, S., Fitamant, J., Jones, P. D., Ghanta, K. S., Kawano, S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411679111 · Cited by 502 · see citing works
“The following mouse strains were used: Ptfa1-Cre (47), LSL-KRAS (48), Shh (49), Trp53 (50), Pdx1-Cre (26), Ink4a/Arf (51), and Gli1-nLacZ (33).”
A small molecule that directs differentiation of human ESCs into the pancreatic lineage.
Chen, S.-B., Borowiak, M., Fox, J. L., Maehr, R., Osafune, K., Davidow, L., Lam, K. T., Lee, P. F., Schreiber, S., Lee, R.-B. L., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.154 · Cited by 500 · see citing works
Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum.
Hoshino, M., Nakamura, S., Mori, K., Kawauchi, T., Terao, M., Nishimura, Y. V., Fukuda, A., Fuse, T., Matsuo, N., Sone, M., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.06.007 · Cited by 479 · see citing works
Self-citationKopp, J. L., Dubois, C. L., Schaffer, A., Hao, E., Shih, H., Seymour, P. A., Ma, J., & Sander, M. (2011) · Development · doi:10.1242/dev.056499 · Cited by 472 · see citing works
“…cell types, which encompass five different endocrine lineages as well as the exocrine acinar and ductal cells, are derived from a pool of early pancreatic progenitor cells that express the transcription factors Pdx1, Ptf1a and Sox9 (Gu et al., 2002; Kawaguchi et al., 2002; Akiyama et al., 2005).”
BackgroundGrowth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells
Hori, Y., Rulifson, I. C., Tsai, B. C., Heit, J. J., Cahoy, J. D., & Kim, S. K. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.252618999 · Cited by 463 · see citing works
Developmental biology of the pancreas: a comprehensive review.
Gittes, G. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2008.10.024 · Cited by 457 · see citing works
“actually emanates from the bile duct (Krapp et al., 1998; Kawaguchi et al., 2002) (see Fig.”
BackgroundMutations in PTF1A cause pancreatic and cerebellar agenesis
Sellick, G. S., Barker, K. T., Stolte‐Dijkstra, I., Fleischmann, C., Coleman, R. J., Garrett, C., Gloyn, A. L., Edghill, E. L., Hattersley, A. T., Wellauer, P. K., et al. (2004) · Nature Genetics · doi:10.1038/ng1475 · Cited by 450 · see citing works
“PTF1A is known to have a role in mammalian pancreatic developmen”
BackgroundMinireview: transcriptional regulation in pancreatic development.
Habener, J., Kemp, D. M., & Thomas, M. K. (2005) · Endocrinology · doi:10.1210/en.2004-1576 · Cited by 437 · see citing works
Regulation of pancreatic beta-cell mass
Bouwens, L., & Rooman, I. (2005) · Physiological Reviews · doi:10.1152/physrev.00025.2004 · Cited by 411 · see citing works
“Ptf1a (pancreas transcription factor, a basic helix-loop-helix transcription factor, or bHLH) is required for specification of ventral pancreas development, whereas the homeobox transcription factor Hlxb9 is required for dorsal specification.”
BackgroundHruban, R., Adsay, N., Albores-saavedra, J., Anver, M., Biankin, A., Boivin, G. P., Furth, E., Furukawa, T., Klein, A., Klimstra, D., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2168 · Cited by 411 · see citing works
“thought to be an exocrine-specific transcription factor, more recent evidence suggests it has a role earlier in pancreatic development and is required for the commitment of all three pancreatic cell lineages (20).”
BackgroundAn illustrated review of early pancreas development in the mouse.
Jørgensen, M. C., Ahnfelt-Rønne, J., Hald, J., Madsen, O., Serup, P., & Hecksher-Sørensen, J. (2007) · Endocrine reviews · doi:10.1210/er.2007-0016 · Cited by 403 · see citing works
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“The LSL-KrasGD12, Trp53F, SmoF, and p48-Cre alleles have been described (Jonkers et al. 2001; Long et al. 2001; Kawaguchi et al. 2002; Tuveson et al. 2004).”
BackgroundIncio, J., Liu, H., Suboj, P., Chin, S. M., Chen, I. X., Pinter, M., Ng, M., Nia, H., Grahovac, J., Kao, S., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1177 · Cited by 397 · see citing works
Gene regulatory factors in pancreatic development
Jensen, J. (2004) · Developmental Dynamics · doi:10.1002/dvdy.10460 · Cited by 397 · see citing works
“As this phenotype reflects that of the Ptf1a mutant mice (Kawaguchi et al., 2002), it raises the possibility that HlxB9 is capable of negatively regulating Ptf1a expression in the pancreatic domains.”
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Izeradjene, K., Combs, C., Best, M., Gopinathan, A., Wagner, A., Grady, W. M., Deng, C.-X., Hruban, R. H., Adsay, N. V., Tuveson, D. A., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.017 · Cited by 379 · see citing works
“, 2001), and p48 (Kawaguchi et al., 2002) or Pdx-1-Cre (kindly provided by Andrew Lowy and described in Hingorani et al.”
BackgroundMethodIjichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Fujitani, Y., Fujitani, S., Wright, C. V. E., & Moses, H. L. (2006) · Genes & Development · doi:10.1101/gad.1475506 · Cited by 379 · see citing works
“…the effect of TGF- signaling in pancreas development and disease, we first generated pancreas epithelium-specific Tgfbr2 knockout mice by crossing the Ptf1acre/+ mice (Kawaguchi et al. 2002) with the Tgfbr2flox/flox mice (Chytil et al. 2002), resulting in the genotype Ptf1acre/+;Tgfbr2flox/flox.”
BackgroundMethodInfluentialSelf-citationMazur, P., Herner, A., Mello, S., Wirth, M., Hausmann, S., Sánchez-Rivera, F. J., Lofgren, S. M., Kuschma, T., Hahn, S., Vangala, D., et al. (2015) · Nature Medicine · doi:10.1038/nm.3952 · Cited by 378 · see citing works
SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer
Mazur, P., Reynoird, N., Khatri, P., Jansen, P., Wilkinson, A. W., Liu, S.-C., Barbash, O., Aller, G. V. V., Huddleston, M. J., Dhanak, D., et al. (2014) · Nature · doi:10.1038/nature13320 · Cited by 370 · see citing works
Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control
Zeilhofer, H., Wildner, H., & Yévenes, G. E. (2012) · Physiological Reviews · doi:10.1152/physrev.00043.2010 · Cited by 364 · see citing works
“Examples of the great potential of transcription factor-dependent cre expression in spinal interneuron populations are Pax2-cre (279) and Ptf1a-cre (188) mice.”
α-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains
Gromada, J., Franklin, I., & Wollheim, C. B. (2007) · Endocrine Reviews · doi:10.1210/er.2006-0007 · Cited by 574 · see citing works
Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration.
Jensen, J., Cameron, E., Garay, M., Starkey, T. W., Gianani, R., & Jensen, J. (2005) · Gastroenterology · doi:10.1053/j.gastro.2004.12.008 · Cited by 361 · see citing works
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On the origin of the β cellPreprint
Oliver-Krasinski, J. M., & Stoffers, D. A. (2008) · Genes & Development · doi:10.1101/gad.1670808 · Cited by 350 · see citing works
“This concept was revised after elegant lineage tracing experiments revealed that Ptf1a is expressed in the pancreatic progenitors that give rise to endocrine, ductal, as well as acinar lineages (Kawaguchi et al. 2002).”
BackgroundNotch-responsive cells initiate the secondary transition in larval zebrafish pancreas
Parsons, M. J., Pisharath, H., Yusuff, S., Moore, J. C., Siekmann, A., Lawson, N., & Leach, S. (2009) · Mechanisms of Development · doi:10.1016/j.mod.2009.07.002 · Cited by 354 · see citing works
“…Teitelman et al., 1993), and (d) mature a-, b-, d-, PP and ghrelin-producing cells located within the pancreatic islets of cartilaginous and bony fish, as well as in all tetrapods (Burlison et al., 2008; Chiang and Melton, 2003; Kawaguchi et al., 2002; Offield et al., 1996; Prado et al., 2004).”
BackgroundYang, A., Herter-Sprie, G., Zhang, H., Lin, E. Y., Biancur, D., Wang, X., Deng, J., Hai, J., Yang, S., Wong, K.-K., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0952 · Cited by 349 · see citing works
“PDAC mice contained Kras allele knocked into the endogenous Kras locus, preceded by an LSL cassette (37); p53 allele where lox-P sites are inserted in the intron 1 and intron 10 respectively (38); and the p48Cre allele that harbors a cre-recombinase gene in the endogenous Ptf1a locus (39).”
Increased islet apoptosis in Pdx1+/- mice.
Johnson, J. D., Ahmed, N. T., Luciani, D., Han, Z.-Q., Tran, H. D., Fujita, J., Misler, S., Edlund, H., & Polonsky, K. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16537 · Cited by 348 · see citing works
“Perhaps most importantly, PDX1 is expressed at some level in several other cell types of the pancreas and foregut, whereas insulin is not (64).”
BackgroundKelly, O. G., Chan, M. Y., Martinson, L. A., Kadoya, K., Ostertag, T. M., Ross, K. G., Richardson, M., Carpenter, M. K., D'Amour, K. A., Kroon, E., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1931 · Cited by 348 · see citing works
“Studies of mouse pancreas development have demonstrated that beta cells arise from pancreatic progenitors and not from the primary endocrine cells, an early born endocrine population that that does not substantially contribute to the adult pancreas and differs in several respects from mature endocrine cells, including…”
BackgroundMeans, A. L., Meszoely, I. M., Suzuki, K., Miyamoto, Y., Rustgi, A. K., Coffey, R. J., Wright, C. V. E., Stoffers, D. A., & Leach, S. D. (2005) · Development · doi:10.1242/dev.01925 · Cited by 344 · see citing works
“These studies have demonstrated that, in the absence of functional Ptf1a/p48 protein, cells normally fated to become pancreas instead become mature duodenal cells (Kawaguchi et al., 2002).”
BackgroundSelf-citationDynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development.Preprint
Gao, N., Lelay, J., Vatamaniuk, M., Rieck, S., Friedman, J. R., & Kaestner, K. (2008) · Genes & Development · doi:10.1101/gad.1752608 · Cited by 338 · see citing works
“5 (Kawaguchi et al. 2002), consistent with the total absence of acinar cells in the Ptf1a-deficient pancreas (Krapp et al. 1998).”
BackgroundMetaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence
Giroux, V., & Rustgi, A. (2017) · Nature Reviews. Cancer · doi:10.1038/nrc.2017.68 · Cited by 331 · see citing works
Pathophysiology of Acute Pancreatitis
Schmid, R. (2005) · Digestion · doi:10.1159/000086137 · Cited by 329
The serosal mesothelium is a major source of smooth muscle cells of the gut vasculature
Wilm, B., Ipenberg, A., Hastie, N., Burch, J., & Bader, D. (2005) · Development · doi:10.1242/dev.02141 · Cited by 328 · see citing works
“However, the current methods, which have been previously used in related studies (Cai et al., 2003; de Lange et al., 2004; Jiang et al., 2002; Kawaguchi et al., 2002), ? splm”
MethodAndricovich, J., Perkail, S., Kai, Y., Casasanta, N., Peng, W., & Tzatsos, A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.02.003 · Cited by 320 · see citing works
“To generate the experimental cohorts, we crossed Kdm6afl/fl mice (Welstead et al., 2012) with Pdx1Cre (Hingorani et al., 2003), Ptf1αCre (Kawaguchi et al., 2002), and LSL-KrasG12D/+ (Tuveson et al., 2004) transgenic strains to generate compound mutant mice with targeted deletion of Kdm6a and…”
BackgroundMethodInfluentialPancreas organogenesis: from lineage determination to morphogenesis.
Shih, H., Wang, A., & Sander, M. (2013) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101512-122405 · Cited by 314 · see citing works
“This was shown by in vivo lineagetracing experiments, which revealed a contribution of Ptf1a-deficient cells to adjacent duodenal and common bile duct endoderm (Burlison et al. 2008, Kawaguchi et al. 2002).”
InfluentialSchonhoff, S. E., Giel-Moloney, M., & Leiter, A. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.03.013 · Cited by 307 · see citing works
“Analysis of the descendants of the transcription factor PTF1-p48 revealed that most islet and duct cells arose from p48+-expressing cells (Kawaguchi et al., 2002).”
BackgroundSox17 regulates organ lineage segregation of ventral foregut progenitor cells
Spence, J., Lange, A. W., Lin, S.-C. J., Kaestner, K., Lowy, A., Kim, I., Whitsett, J., & Wells, J. M. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.05.012 · Cited by 306 · see citing works
“…detailed many transcription factors that are required for specification of individual organs, including the liver (Foxa2, Foxa1 and Hhex) and pancreas (Ptf1a/p48, Pdx1, Hhex) (Bort et al., 2004; Bort et al., 2006; Kawaguchi et al., 2002; Krapp et al., 1998; Lee et al., 2005; Offield et al., 1996).”
BackgroundPancreatic Cancer: Basic and Clinical Aspects
Schneider, G., Siveke, J. T., Eckel, F., & Schmid, R. M. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.04.001 · Cited by 285 · see citing works
Pancreas and beta-cell development: from the actual to the possible
Murtaugh, L. (2006) · Development · doi:10.1242/dev.02770 · Cited by 303 · see citing works
“Another transcription factor, Ptf1a, is also expressed in the early pancreas, and its endodermal expression remains pancreas-specific throughout development (Kawaguchi et al., 2002).”
InfluentialNostro, M., Sarangi, F., Yang, C.-X., Holland, A. M., Elefanty, A., Stanley, E., Greiner, D. L., & Keller, G. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.02.017 · Cited by 302 · see citing works
“…of a combination of transcription factors, including Pdx1, Ptf1a,Nkx6-1,Cpa,Myc, and Sox9 (Burlison et al., 2008; Gu et al., 2002; Haumaitre et al., 2005; Henseleit et al., 2005; Kawaguchi et al., 2002; Kopp et al., 2011; Seymour and Sander, 2007; Solar et al., 2009; Zhou et al., 2007).”
BackgroundJennings, R. E., Berry, A. A., Strutt, J., Gerrard, D. T., & Hanley, N. (2015) · Development · doi:10.1242/dev.120063 · Cited by 301 · see citing works
Tremblay, K. D., & Zaret, K. S. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.01.003 · Cited by 299 · see citing works
“Foregut organogenic fate mapping in the mouse has not been reported, and genetic methods to map gut tissue lineages have been limited to tissue-specific promoters that are activated after tissues are specified (Gu et al., 2002; Kawaguchi et al., 2002).”
BackgroundPan, F. C., Bankaitis, E., Boyer, D. F., Xu, X.-B., de Casteele, M. V., Magnuson, M., Heimberg, H., & Wright, C. (2013) · Development · doi:10.1242/dev.090159 · Cited by 299 · see citing works
“Paraffin sections, whole-mount -galactosidase detection, H&E staining, processing was as described (Kawaguchi et al., 2002).”
BackgroundMethodInfluentialSelf-citationGenetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation
Zaret, K. S. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2318 · Cited by 285 · see citing works
α-Ketoglutarate links p53 to cell fate during tumour suppression
Morris, J. P., Yashinskie, J. J., Koche, R., Chandwani, R., Tian, S., Chen, C.-C., Baslan, T., Marinkovic, Z. S., Sánchez-Rivera, F. J., Leach, S. D., et al. (2019) · Nature · doi:10.1038/s41586-019-1577-5 · Cited by 296 · see citing works
Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice.
Martín, M., Gallego-Llamas, J., Ribes, V., Kedinger, M., Niederreither, K., Chambon, P., Dollé, P., & Gradwohl, G. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.05.035 · Cited by 295 · see citing works
“Another transcription factor, the bHLH (basic helix–loop–helix) protein Ptf1a, is essential for the acquisition of the pancreatic fate by the foregut endoderm (Kawaguchi et al., 2002).”
BackgroundInfluentialLack of TCF2/vHNF1 in mice leads to pancreas agenesis.
Haumaître, C., Barbacci, E., Jenny, M., Ott, M., Gradwohl, G., & Cereghini, S. (2005) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0405776102 · Cited by 281 · see citing works
Minami, K., Okuno, M., Miyawaki, K., Okumachi, A., Ishizaki, K., Oyama, K., Kawaguchi, M., Ishizuka, N., Iwanaga, T., & Seino, S. (2005) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0507567102 · Cited by 272 · see citing works
Sox9 coordinates a transcriptional network in pancreatic progenitor cells
Lynn, F., Smith, S. B., Wilson, M. E., Yang, K.-Y., Nekrep, N., & German, M. (2007) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0704054104 · Cited by 271 · see citing works
A gene–environment-induced epigenetic program initiates tumorigenesis
Alonso‐Curbelo, D., Ho, Y.-J., Burdziak, C., Mååg, J. L. V., Morris, J. P., Chandwani, R., Chen, H.-A., Tsanov, K. M., Barriga, F. M., Luan, W., et al. (2021) · Nature · doi:10.1038/s41586-020-03147-x · Cited by 306 · see citing works
Yoshitomi, H., & Zaret, K. (2004) · Development · doi:10.1242/dev.00960 · Cited by 268 · see citing works
“Genetic lineage tracing studies have shown that early endoderm cells expressing Ptf1a contribute to all pancreatic cell lineages and thereby constitute the definitive pancreatic progenitor population (Krapp et al., 1998; Kawaguchi et al., 2002).”
InfluentialBort, R., Martinez-Barbera, J. P., Beddington, R. S. P., & Zaret, K. S. (2004) · Development · doi:10.1242/dev.00965 · Cited by 267 · see citing works
“The bHLH transcription factor gene Ptf1ap48 is necessary for the specification of all ventral but not all dorsal pancreatic cells (Kawaguchi et al., 2002; Krapp et al., 1998); the homeobox genes I l1 and Hlxb9 are necessary for the specification of all dorsal but not ventral pancreatic cells…”
BackgroundInfluentialSignals from lateral plate mesoderm instruct endoderm toward a pancreatic fate.
Kumar, M., Jordan, N., Melton, D., & Grapin-Botton, A. (2003) · Developmental Biology · doi:10.1016/s0012-1606(03)00183-0 · Cited by 263 · see citing works
“…on pancreatic fate, we assessed expression of the endocrine hormones glucagon and insulin (Slack, 1995), a marker of both the early pancreatic epithelium and later the exocrine lineage, p48 (Kawaguchi et al., 2002; Krapp et al., 1996), and a marker of pancreas progenitors and (cid:1) cells, Nkx6.”
BackgroundMolecular regulation of pancreatic β-cell mass development, maintenance, and expansion
Ackermann, A. M., & Gannon, M. (2007) · Journal of Molecular Endocrinology · doi:10.1677/jme-06-0053 · Cited by 262 · see citing works
“5 and is required for the growth of the pancreatic buds (Krapp et al. 1998, Kawaguchi et al. 2002).”
BackgroundSelf-citationMouse Retinal Cell Atlas: Molecular Identification of over Sixty Amacrine Cell Types
Yan, W., Laboulaye, M. A., Tran, N. M., Whitney, I. E., Benhar, I., & Sanes, J. R. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.0471-20.2020 · Cited by 329 · see citing works
“The Ptf1a-cre (Kawaguchi et al., 2002) line was obtained from Lisa Goodrich (Harvard Medical School), The Thy1-STP-YFP Line 15 was generated in our laboratory (stock #005630, The Jackson Laboratory; Buffelli et al.”
MethodInfluentialβ-Catenin is essential for pancreatic acinar but not islet development
Murtaugh, L., Law, A., Dor, Y., & Melton, D. (2005) · Development · doi:10.1242/dev.02063 · Cited by 260 · see citing works
“Although Ptf1a is expressed broadly in the early pancreatic primordium, in progenitors of all mature cell types (Kawaguchi et al., 2002), it becomes specifically upregulated in peripherally epithelial clusters 1-2 days prior to acinar differentiation, likely marking the nascent acini (Esni et al.”
BackgroundIjichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Bierie, B., Tada, M., Mohri, D., Miyabayashi, K., Asaoka, Y., Maeda, S., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42754 · Cited by 256 · see citing works
“Tgfbr2flox/flox (44) and Ptf1acre/+ (45) mice were described previously.”
BackgroundSelf-citationEpithelial dynamics of pancreatic branching morphogenesis
Villasenõr, A., Chong, D. C., Henkemeyer, M., & Cleaver, O. (2010) · Development · doi:10.1242/dev.052993 · Cited by 255 · see citing works
Genes, signals, and lineages in pancreas development.
Murtaugh, L., & Melton, D. A. (2003) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.19.111301.144752 · Cited by 255 · see citing works
SIRT6 suppresses pancreatic cancer through control of Lin28b
Kugel, S., Sebastián, C., Fitamant, J., Ross, K., Saha, S., Jain, E., Gladden, A., Arora, K. S., Kato, Y., Rivera, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.033 · Cited by 251 · see citing works
“, 2012) were crossed with the p48-Cre strain (Kawaguchi et al., 2002), the conditional p53 strain (Marino et al.”
BackgroundConversion of biliary system to pancreatic tissue in Hes1-deficient mice
Sumazaki, R., Shiojiri, N., Isoyama, S., Masu, M., Keino-Masu, K., Osawa, M., Nakauchi, H., Kageyama, R., & Matsui, A. (2004) · Nature Genetics · doi:10.1038/ng1273 · Cited by 242 · see citing works
Single-cell transcript analysis of pancreas development.
Chiang, M.-K., & Melton, D. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00035-2 · Cited by 240 · see citing works
Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis.
Gu, G.-Q., Brown, J. R., & Melton, D. (2003) · Mechanisms of Development · doi:10.1016/s0925-4773(02)00330-1 · Cited by 236 · see citing works
Esni, F., Ghosh, B., Biankin, A., Lin, J. W., Albert, M. A., Yu, X., MacDonald, R. J., Civin, C., Real, F., Pack, M., et al. (2004) · Development · doi:10.1242/dev.01280 · Cited by 235 · see citing works
“…work †Author for correspondence (e-mail: stleach@jhmi.edu) Accepted 25 May 2004 Development 131, 4213-4224 Published by The Company of Biologists 2004 doi:10.1242/dev.01280 Research article 4214 in foregut endoderm (Gu et al., 2003; Gu et al., 2002; Kawaguchi et al., 2002; Kim and MacDonald, 2002).”
BackgroundMethodResultInfluentialSelf-citationA Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation
Shih, H., Kopp, J. L., Sandhu, M., Dubois, C. L., Seymour, P. A., Grapin-Botton, A., & Sander, M. (2012) · Development · doi:10.1242/dev.078634 · Cited by 233 · see citing works
Hart, A., Papadopoulou, S., & Edlund, H. (2003) · Developmental Dynamics · doi:10.1002/dvdy.10368 · Cited by 233
“…transcription factor Ptf1a/p48 (Krapp et al., 1998), which is expressed in early pancreatic progenitor cells from e10 (Selander and Edlund, 2002; Kawaguchi et al., 2002) and later becomes restricted to differentiated exocrine cells (Krapp et al., 1998), was also expressed throughout the…”
BackgroundPancreatic ductal cells in development, regeneration, and neoplasia
Reichert, M., & Rustgi, A. K. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57131 · Cited by 235 · see citing works
Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis
Morton, J., Mongeau, M. E., Klimstra, D., Morris, J. P., Lee, Y.-C., Kawaguchi, Y., Wright, C., Hebrok, M., & Lewis, B. (2007) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0701158104 · Cited by 230 · see citing works
Self-citationPtf1a determines horizontal and amacrine cell fates during mouse retinal development
Fujitani, Y., Fujitani, S., Luo, H.-J., Qiu, F., Burlison, J. S., Long, Q.-M., Kawaguchi, Y., Edlund, H., MacDonald, R. J., Furukawa, T., et al. (2006) · Development · doi:10.1242/dev.02598 · Cited by 227 · see citing works
“mice have a knock-in Ptf1a null allele, where the Ptf1a-coding region is replaced by Cre-recombinase (Kawaguchi et al., 2002).”
BackgroundMethodInfluentialSelf-citationPtf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn
Glasgow, S. M., Henke, R. M., MacDonald, R. J., Wright, C. V. E., & Johnson, J. E. (2005) · Development · doi:10.1242/dev.02167 · Cited by 225 · see citing works
“The mouse strain Ptf1aCre/+, which has the Ptf1a protein-coding region replaced by that of Cre recombinase (Kawaguchi et al., 2002), was crossed with the Cre reporter strain R26R-stop-lacZ+/–.”
BackgroundInfluentialSelf-citationTranscriptional networks controlling pancreatic development and beta cell function
Servitja, J., & Ferrer, J. (2004) · Diabetologia · doi:10.1007/s00125-004-1368-9 · Cited by 225 · see citing works
“Thus Pdx1 and Ptf1a are indispensable for the formation or progression of both buds [29, 36, 37, 38].”
BackgroundEpithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis
Poggetto, E. D., Ho, I., Balestrieri, C., Yen, E.-Y., Zhang, S.-J., Citron, F., Shah, R., Corti, D., Diaferia, G., Li, C.-Y., et al. (2021) · Science · doi:10.1126/science.abj0486 · Cited by 222 · see citing works
Norgaard, G. A., Jensen, J., & Jensen, J. (2003) · Developmental Biology · doi:10.1016/j.ydbio.2003.08.013 · Cited by 222
“To evaluate a possible mechanism to account for the reduction of exocrine cell differentiation, we analyzed expression of the Ptf1a gene, which is normally expressed both in pancreatic progenitor cells, and later is involved in the exocrine fate choice (Kawaguchi et al., 2002).”
BackgroundOrdered and deterministic cancer genome evolution after p53 loss
Baslan, T., Morris, J. P., Zhao, Z., Reyes, J., Ho, Y.-J., Tsanov, K. M., Bermeo, J., Tian, S., Zhang, S., Askan, G., et al. (2022) · Nature · doi:10.1038/s41586-022-05082-5 · Cited by 221 · see citing works
Nakhai, H., Sel, S., Favor, J., Mendoza-Torres, L., Paulsen, F., Duncker, G. I. W., & Schmid, R. (2007) · Development · doi:10.1242/dev.02781 · Cited by 219 · see citing works
“Ptf1a plays a fundamental role in exocrine and endocrine pancreas development in mice (Kawaguchi et al., 2002).”
BackgroundBeres, T. M., Masui, T., Swift, G. H., Shi, L., Henke, R., & MacDonald, R. J. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.1.117-130.2006 · Cited by 216 · see citing works
“Targeted deletion of the p48 gene causes pancreatic and cerebellar agenesis (14, 17, 36), so understanding the mechanism of transcriptional activation by PTF1 in differentiated acini will likely give insights into PTF1 action during pancreas and brain development as well.”
BackgroundSelf-citationHow to make a functional β-cell
Pagliuca, F., & Melton, D. (2013) · Development · doi:10.1242/dev.093187 · Cited by 215 · see citing works
“Lineage tracing of Ptf1a-expressing cells revealed similar results (Kawaguchi et al., 2002).”
ResultNatural history of β-cell adaptation and failure in type 2 diabetes
Alejandro, E. U., Gregg, B. E., Blandino-Rosano, M., CRAS-MÉNEUR, C. M. H., & Bernal‐Mizrachi, E. (2014) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2014.12.002 · Cited by 235 · see citing works
- Authors
- Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R. J., & Wright, C. V. E.
- Affiliations
- Vanderbilt University (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Wright, Christopher V.E.
- Venue
- Nature Genetics
- Published
- 2002-08-19
- Volume
- 32
- Issue
- 1
- Pages
- 128-134
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1993055783
- Cited by
- 1,007
- References
- 26
- Citations by year
- 2026: 18 · 2025: 30 · 2024: 18 · 2023: 39 · 2022: 23 · 2021: 39 · 2020: 39 · 2019: 44 · 2018: 43 · 2017: 44 · 2016: 44 · 2015: 62 · 2014: 54 · 2013: 65 · 2012: 68
- FWCI
- 35.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- Ptf1a, pancreatic development, foregut endoderm, pancreatic progenitors, duodenal epithelium, pancreatic stem cells, PDX1, cis-regulatory sequences, lineage tracing, organogenesis
- MeSH terms
- Animals, Cell Differentiation, Duodenum, Gene Expression Regulation, Pancreas, Transcription Factors, Trans-Activators, Homeodomain Proteins, Cell Lineage, Animals, Genetically Modified, Mice
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