PDX1

PDX1 (pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster.^[5] In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1.^[6][7] The gene was originally identified in the clawed frog Xenopus laevis ^[8] and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes.^[5] Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals.^[9] Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.^[10]

PDX1
Identifiers
Aliases	PDX1, GSF, IDX-1, IPF1, IUF1, MODY4, PAGEN1, PDX-1, STF-1, pancreatic and duodenal homeobox 1
External IDs	OMIM: 600733 MGI: 102851 HomoloGene: 175 GeneCards: PDX1
Gene location (Human) Chr. Chromosome 13 (human)^[1] Band 13q12.2 Start 27,920,000 bp^[1] End 27,926,313 bp^[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)^[2] Band 5 G3|5 86.84 cM Start 147,206,769 bp^[2] End 147,212,658 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans body of pancreas duodenum gallbladder liver rectum right lobe of liver stomach kidney body of stomach Top expressed in endocrine pancreas islet of Langerhans duodenum pyloric antrum humerus Meckel's cartilage mucous cell of stomach secondary oocyte occiput occipital bone More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding sequence-specific DNA binding DNA-binding transcription factor activity chromatin binding RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific transcription factor binding protein-containing complex binding protein heterodimerization activity promoter-specific chromatin binding Cellular component cytoplasm cytosol nuclear speck intracellular anatomical structure nucleus nucleoplasm Biological process exocrine pancreas development negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway cell differentiation regulation of transcription, DNA-templated glucose homeostasis regulation of transcription by RNA polymerase II insulin secretion negative regulation of transcription by RNA polymerase II generation of precursor metabolites and energy transcription, DNA-templated multicellular organism development positive regulation of transcription, DNA-templated regulation of cell population proliferation positive regulation of cell population proliferation nitric oxide mediated signal transduction glucose metabolic process animal organ morphogenesis pancreas development liver development positive regulation of insulin secretion involved in cellular response to glucose stimulus morphogenesis of embryonic epithelium digestive tract development negative regulation of type B pancreatic cell apoptotic process negative regulation of cell population proliferation positive regulation of transcription by RNA polymerase II endocrine pancreas development type B pancreatic cell differentiation transcription by RNA polymerase II detection of glucose smoothened signaling pathway central nervous system development response to wounding response to glucose response to iron(II) ion response to chlorate regulation of gene expression positive regulation of cell death response to organic cyclic compound animal organ regeneration response to nutrient levels positive regulation of insulin secretion response to vitamin response to lipid response to cytokine response to nicotine response to leucine response to alkaloid positive regulation of DNA binding negative regulation of transcription, DNA-templated stem cell differentiation response to glucocorticoid transdifferentiation response to fatty acid Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3651 18609 Ensembl ENSG00000139515 ENSMUSG00000029644 UniProt P52945 P52946 RefSeq (mRNA) NM_000209 NM_008814 RefSeq (protein) NP_000200 NP_032840 Location (UCSC) Chr 13: 27.92 – 27.93 Mb Chr 5: 147.21 – 147.21 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Pancreatic development

In pancreatic development, Pdx1 is expressed by a population of cells in the posterior foregut region of the definitive endoderm, and Pdx1⁺ epithelial cells give rise to the developing pancreatic buds, and eventually, the whole of the pancreas—its exocrine, endocrine, and ductal cell populations.^[11] Pancreatic Pdx1⁺ cells first arise at mouse embryonic day 8.5-9.0 (E8.5-9.0), and Pdx1 expression continues until E12.0-E12.5.^[12] Homozygous Pdx1 knockout mice form pancreatic buds but fail to develop a pancreas,^[13] and transgenic mice in which tetracycline application results in death of Pdx1⁺ cells are almost completely apancreatic if doxycycline (tetracycline derivative) is administered throughout the pregnancy of these transgenic mice, illustrating the necessity of Pdx1⁺ cells in pancreatic development.^[12]

Pdx1 is accepted as the earliest marker for pancreatic differentiation, with the fates of pancreatic cells controlled by downstream transcription factors.^[13] The initial pancreatic bud is composed of Pdx1⁺ pancreatic progenitor cells that co-express Hlxb9, Hnf6, Ptf1a and NKX6-1. These cells further proliferate and branch in response to FGF-10 signaling. Afterwards, differentiation of the pancreatic cells begins; a population of cells has Notch signaling inhibited, and subsequently, expresses Ngn3. This Ngn3⁺ population is a transient population of pancreatic endocrine progenitors that gives rise to the α, β, Δ, PP, and ε cells of the islets of Langerhans.^[12] Other cells will give rise to the exocrine and ductal pancreatic cell populations.

β-cell maturation and survival

The final stages of pancreas development involves the production of different endocrine cells, including insulin-producing β-cells and glucagon-producing α-cells. Pdx1 is necessary for β-cell maturation: developing β-cells co-express Pdx1, NKX6-1, and insulin, a process that results in the silencing of MafB and the expression of MafA, a necessary switch in maturation of β-cells.^[11] At this stage of pancreas development, the experimental decrease in the expression of Pdx1 results in a production of a smaller number of β-cells and an associated increase in the number of α-cells.^[14]

In the mature pancreas, Pdx1 expression seems to be required for the maintenance and survival of β-cells. For instance, experimentally reducing the level of Pdx1 expression at this stage makes β-cells produce higher amounts of glucagon,^[15] suggesting that Pdx1 inhibits the conversion of β-cells into α-cells. Furthermore, Pdx1 appears to be important in mediating the effect of insulin on the apoptotic programmed cell death of β-cells: a small concentration of insulin protects β-cells from apoptosis, but not in cells where Pdx1 expression has been inhibited.^[16][17]

Duodenum

Pdx1 is necessary for the development of the proximal duodenum and maintenance of the gastro-duodenal junction.^[18] Duodenal enterocytes, Brunner's glands and entero-endocrine cells (including those in the gastric antrum) are dependent on Pdx1 expression. It is a ParaHox gene, which together with Sox2 and Cdx2, determines the correct cellular differentiation in the proximal gut.^[18] In mature mice duodenum, several genes have been identified which are dependent on Pdx1 expression and include some affecting lipid and iron absorption.^[19]

Pathology

Experiments in animal models have shown that a reduction in Pdx1 expression can cause symptoms that are characteristic of Diabetes mellitus type 1 and Diabetes mellitus type 2.^[20] Furthermore, expression of Pdx1 is lost in gastric cancers, suggesting a role for the gene as a tumor suppressor.^[21] Maturity onset diabetes of the young (Type 4) can be caused by heterozygous mutations in Pdx1.^[22][23] The fat sand rat Psammomys obesus, a species with susceptibility to Diabetes mellitus type 2 symptoms, has a highly divergent Pdx1 gene sequence compared with other mammals.^[24]

Interactions

Pdx1 has been shown to interact with MAFA.^[25]

References

1. GRCh38: Ensembl release 89: ENSG00000139515 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029644 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Brooke, N. M., Garcia-Fernàndez, J., & Holland, P. W. (1998). The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster. Nature, 392(6679), 920.
6. "PDX1". HGNC. Retrieved 22 April 2016.
7. Stoffel M, Stein R, Wright CV, Espinosa R, Le Beau MM, Bell GI (July 1995). "Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1". Genomics. 28 (1): 125–6. doi:10.1006/geno.1995.1120. PMID 7590740.
8. Wright, C. V., Schnegelsberg, P., & De Robertis, E. M. (1989). XlHbox 8: a novel Xenopus homeo protein restricted to a narrow band of endoderm. Development, 105(4), 787-794.
9. "OrthoMaM phylogenetic marker: PDX1 coding sequence". OrthoMam v10. 2019. Retrieved 24 February 2019.
10. Mulley JF, Holland PW (October 2010). "Parallel retention of Pdx2 genes in cartilaginous fish and coelacanths". Molecular Biology and Evolution. 27 (10): 2386–91. doi:10.1093/molbev/msq121. PMC 2944030. PMID 20463047.
11. D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE (November 2006). "Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells". Nat. Biotechnol. 24 (11): 1392–401. doi:10.1038/nbt1259. PMID 17053790. S2CID 11040949.
12. Stanger BZ, Tanaka AJ, Melton DA (February 2007). "Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver". Nature. 445 (7130): 886–91. Bibcode:2007Natur.445..886S. doi:10.1038/nature05537. PMID 17259975. S2CID 4379651.
13. Liew CG, Shah NN, Briston SJ, Shepherd RM, Khoo CP, Dunne MJ, Moore HD, Cosgrove KE, Andrews PW (2008). "PAX4 enhances beta-cell differentiation of human embryonic stem cells". PLOS ONE. 3 (3): e1783. Bibcode:2008PLoSO...3.1783L. doi:10.1371/journal.pone.0001783. PMC 2262135. PMID 18335054.  
14. Gannon M, Ables ET, Crawford L, et al. pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis. Dev Biol. 2007;314(2):406-17. doi:10.1016/j.ydbio.2007.10.038
15. Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev. 1998;12(12):1763-8.
16. Johnson JD, Ahmed NT, Luciani DS, Han Z, Tran H, Fujita J, Misler S, Edlund H, Polonsky KS (April 2003). "Increased islet apoptosis in Pdx1+/- mice". J. Clin. Invest. 111 (8): 1147–60. doi:10.1172/JCI16537. PMC 152933. PMID 12697734.
17. Johnson JD, Bernal-Mizrachi E, Alejandro EU, Han Z, Kalynyak TB, Li H, Beith JL, Gross J, Warnock GL, Townsend RR, Permutt MA, Polonsky KS (December 2006). "Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome". Proc. Natl. Acad. Sci. U.S.A. 103 (51): 19575–80. Bibcode:2006PNAS..10319575J. doi:10.1073/pnas.0604208103. PMC 1748267. PMID 17158802.
18. Holland AM, Garcia S, Naselli G, Macdonald RJ, Harrison LC (2013). "The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut". Int. J. Dev. Biol. 57 (5): 391–8. doi:10.1387/ijdb.120048ah. PMID 23873371.
19. Chen C, Sibley E (2012). "Expression profiling identifies novel gene targets and functions for Pdx1 in the duodenum of mature mice". Am. J. Physiol. Gastrointest. Liver Physiol. 302 (4): G407–19. doi:10.1152/ajpgi.00314.2011. PMC 3287393. PMID 22135308.
20. Fujimoto, Kei, and Kenneth S. Polonsky. "Pdx1 and other factors that regulate pancreatic β‐cell survival." Diabetes, Obesity and Metabolism 11 (2009): 30-37.
21. Ma J, Chen M, Wang J, Xia HH, Zhu S, Liang Y, Gu Q, Qiao L, Dai Y, Zou B, Li Z, Zhang Y, Lan H, Wong BC (2008). "Pancreatic duodenal homeobox-1 (PDX1) functions as a tumor suppressor in gastric cancer". Carcinogenesis. 29 (7): 1327–33. doi:10.1093/carcin/bgn112. PMID 18477649.
22. "Entrez Gene: PDX1 pancreatic and duodenal homeobox 1".
23. Fajans SS, Bell GI, Polonsky KS (September 2001). "Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young". N. Engl. J. Med. 345 (13): 971–80. doi:10.1056/NEJMra002168. PMID 11575290.
24. Hargreaves AD, Zhou L, Christensen J, Marlétaz F, Liu S, Li F, et al. (July 2017). "Genome sequence of a diabetes-prone rodent reveals a mutation hotspot around the ParaHox gene cluster". Proceedings of the National Academy of Sciences of the United States of America. 114 (29): 7677–7682. Bibcode:2017PNAS..114.7677H. doi:10.1073/pnas.1702930114. PMC 5530673. PMID 28674003.
25. Zhao L, Guo M, Matsuoka TA, Hagman DK, Parazzoli SD, Poitout V, Stein R (March 2005). "The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription". J. Biol. Chem. 280 (12): 11887–94. doi:10.1074/jbc.M409475200. PMID 15665000.

Further reading

• Zhou Q, Brown J, Kanarek A, Rajagopal J, Douglas A, Melton DA (2008). "In vivo reprogramming of adult pancreatic exocrine cells to β-cells". Nature. 455 (7213): 627–32. Bibcode:2008Natur.455..627Z. doi:10.1038/nature07314. PMC 9011918. PMID 18754011. S2CID 205214877.
• Hui H, Perfetti R (2002). "Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood". Eur. J. Endocrinol. 146 (2): 129–41. doi:10.1530/eje.0.1460129. PMID 11834421.
• Leonard J, Peers B, Johnson T, et al. (1994). "Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells". Mol. Endocrinol. 7 (10): 1275–83. doi:10.1210/mend.7.10.7505393. PMID 7505393.
• Stoffel M, Stein R, Wright CV, et al. (1995). "Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1". Genomics. 28 (1): 125–6. doi:10.1006/geno.1995.1120. PMID 7590740.
• Inoue H, Riggs AC, Tanizawa Y, et al. (1996). "Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene". Diabetes. 45 (6): 789–94. doi:10.2337/diabetes.45.6.789. PMID 8635654.
• Waeber G, Thompson N, Nicod P, Bonny C (1997). "Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor". Mol. Endocrinol. 10 (11): 1327–34. doi:10.1210/mend.10.11.8923459. PMID 8923459.
• Watada H, Kajimoto Y, Kaneto H, et al. (1997). "Involvement of the homeodomain-containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription". Biochem. Biophys. Res. Commun. 229 (3): 746–51. doi:10.1006/bbrc.1996.1875. PMID 8954967.
• Marshak S, Totary H, Cerasi E, Melloul D (1997). "Purification of the beta-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells". Proc. Natl. Acad. Sci. U.S.A. 93 (26): 15057–62. doi:10.1073/pnas.93.26.15057. PMC 26355. PMID 8986763.
• Stoffers DA, Zinkin NT, Stanojevic V, et al. (1997). "Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence". Nat. Genet. 15 (1): 106–10. doi:10.1038/ng0197-106. PMID 8988180. S2CID 25406130.
• Sharma S, Jhala US, Johnson T, et al. (1997). "Hormonal regulation of an islet-specific enhancer in the pancreatic homeobox gene STF-1". Mol. Cell. Biol. 17 (5): 2598–604. doi:10.1128/mcb.17.5.2598. PMC 232109. PMID 9111329.
• Carty MD, Lillquist JS, Peshavaria M, et al. (1997). "Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells". J. Biol. Chem. 272 (18): 11986–93. doi:10.1074/jbc.272.18.11986. PMID 9115263.
• Macfarlane WM, Smith SB, James RF, et al. (1997). "The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells". J. Biol. Chem. 272 (33): 20936–44. doi:10.1074/jbc.272.33.20936. PMID 9252422.
• Macfarlane WM, Frayling TM, Ellard S, et al. (1999). "Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes". J. Clin. Invest. 104 (9): R33–9. doi:10.1172/JCI7449. PMC 481047. PMID 10545530.
• Hani EH, Stoffers DA, Chèvre JC, et al. (1999). "Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus". J. Clin. Invest. 104 (9): R41–8. doi:10.1172/JCI7469. PMC 409821. PMID 10545531.
• Glick E, Leshkowitz D, Walker MD (2000). "Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter". J. Biol. Chem. 275 (3): 2199–204. doi:10.1074/jbc.275.3.2199. PMID 10636926.
• Schwartz PT, Perez-Villamil B, Rivera A, et al. (2000). "Pancreatic homeodomain transcription factor IDX1/IPF1 expressed in developing brain regulates somatostatin gene transcription in embryonic neural cells". J. Biol. Chem. 275 (25): 19106–14. doi:10.1074/jbc.M000655200. hdl:10261/79745. PMID 10751390.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Liu Y, MacDonald RJ, Swift GH (2001). "DNA binding and transcriptional activation by a PDX1.PBX1b.MEIS2b trimer and cooperation with a pancreas-specific basic helix-loop-helix complex". J. Biol. Chem. 276 (21): 17985–93. doi:10.1074/jbc.M100678200. PMID 11279116.
• Samaras SE, Cissell MA, Gerrish K, et al. (2002). "Conserved sequences in a tissue-specific regulatory region of the pdx-1 gene mediate transcription in Pancreatic beta cells: role for hepatocyte nuclear factor 3 beta and Pax6". Mol. Cell. Biol. 22 (13): 4702–13. doi:10.1128/MCB.22.13.4702-4713.2002. PMC 133887. PMID 12052878.
• Zhou J, Pineyro MA, Wang X, et al. (2002). "Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors". J. Cell. Physiol. 192 (3): 304–14. doi:10.1002/jcp.10143. PMID 12124776. S2CID 11530928.

External links

• GeneReviews/NCBI/NIH/UW entry on Permanent Neonatal Diabetes Mellitus
• PDX1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.