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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 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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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
“, 2001), and p48 (Kawaguchi et al., 2002) or Pdx-1-Cre (kindly provided by Andrew Lowy and described in Hingorani et al.”
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On the origin of the β cellPreprint
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“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
“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
“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
Pathophysiology of Acute Pancreatitis
Schmid, R. M. (2005) · Digestion · doi:10.1159/000086137 · Cited by 37
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
“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
“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.-P., Wang, A., & Sander, M. (2013) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101512-122405 · Cited by 347
“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. B. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.03.013 · Cited by 285
“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. R., Lange, A. W., Lin, S. J., Kaestner, K. H., Lowy, A. M., Kim, I., Whitsett, J. A., & Wells, J. M. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.05.012 · Cited by 311
“…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 289
Pancreas and beta-cell development: from the actual to the possible
Murtaugh, L. C. (2006) · Development · doi:10.1242/dev.02770 · Cited by 295
“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
“…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. P. B., Gerrard, D. T., & Hanley, N. A. (2015) · Development · doi:10.1242/dev.120063 · Cited by 357
Tremblay, K. D., & Zaret, K. S. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.01.003 · Cited by 299
“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
“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 295
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
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
“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
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 · doi:10.1073/pnas.0507567102 · Cited by 261
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
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 311
Yoshitomi, H., & Zaret, K. S. (2004) · Development · doi:10.1242/dev.00960 · Cited by 264
“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).”
InfluentialHex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas
Bort, R., Martinez-Barbera, J. P., Beddington, R. S. P., & Zaret, K. S. (2004) · Development · doi:10.1242/dev.00965 · Cited by 267
“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. E., Jordan, N., Melton, D. A., & Grapin‐Botton, A. (2003) · Developmental Biology · doi:10.1016/s0012-1606(03)00183-0 · Cited by 247
“…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
“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 343
“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. C., Law, A. C., Dor, Y., & Melton, D. A. (2005) · Development · doi:10.1242/dev.02063 · Cited by 241
“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
“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
Genes, Signals, and Lineages in Pancreas Development
Murtaugh, L. C., & Melton, D. A. (2003) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.19.111301.144752 · Cited by 235
SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b
Kugel, S., Sebastián, C., Fitamant, J., Ross, K. N., Saha, S. K., Jain, E., Gladden, A. D., Arora, K. S., Kato, Y., Rivera, M. N., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.033 · Cited by 294
“, 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
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
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
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
“…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
Hart, A. W., Papadopoulou, S., & Edlund, H. (2003) · Developmental Dynamics · doi:10.1002/dvdy.10368 · Cited by 221
“…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 246
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
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
“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
“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. P. (2004) · Diabetologia · doi:10.1007/s00125-004-1368-9 · Cited by 215
“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.-L., Balestrieri, C., Yen, E.-Y., Zhang, S., Citron, F., Shah, R., Corti, D., Diaferia, G. R., Li, C.-Y., et al. (2021) · Science · doi:10.1126/science.abj0486 · Cited by 259
Norgaard, G. A., Jensen, J. N., & Jensen, J. (2003) · Developmental Biology · doi:10.1016/j.ydbio.2003.08.013 · Cited by 215
“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
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
“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. M., & MacDonald, R. J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.26.1.117-130.2006 · Cited by 203
“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. W., & Melton, D. A. (2013) · Development · doi:10.1242/dev.093187 · Cited by 226
“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 250
Metadata
- 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 › Endocrinology, Diabetes and Metabolism › 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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