Pdx1

Pdx1 (Pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a transcription factor necessary for pancreatic development and β-cell maturation. "Pdx1", otherwise known as "Ipf1", is the human gene encoding it.cite journal | author = Stoffel M, Stein R, Wright CV, Espinosa R, Le Beau MM, Bell GI | title = Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1 | journal = Genomics | volume = 28 | issue = 1 | pages = 125–6 | year = 1995 | month = July | pmid = 7590740 | doi = 10.1006/geno.1995.1120 | url = | issn = ]

Function

Pancreatic development

In embryonic 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.cite journal | author = D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE | title = Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells | journal = Nat. Biotechnol. | volume = 24 | issue = 11 | pages = 1392–401 | year = 2006 | month = November | pmid = 17053790 | doi = 10.1038/nbt1259 | url = | issn = ] 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,cite journal | author = Stanger BZ, Tanaka AJ, Melton DA | title = Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver | journal = Nature | volume = 445 | issue = 7130 | pages = 886–91 | year = 2007 | month = February | pmid = 17259975 | doi = 10.1038/nature05537 | url = | issn = ] after which Pdx1 expression decreases and the pancreas is formed—other transcription factors are expressed, controlling the fates of the cells of the newly-formed pancreas.cite journal | author = Liew CG, Shah NN, Briston SJ, Shepherd RM, Khoo CP, Dunne MJ, Moore HD, Cosgrove KE, Andrews PW | title = PAX4 enhances beta-cell differentiation of human embryonic stem cells | journal = PLoS ONE | volume = 3 | issue = 3 | pages = e1783 | year = 2008 | pmid = 18335054 | pmc = 2262135 | doi = 10.1371/journal.pone.0001783 | url = | issn = ] Homozygous "Pdx1" knockout mice form pancreatic buds but fail to develop a pancreas, 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.

β-cell Maturation

Pdx1 is also 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. Pdx1 appears to also play a role in the fating of endocrine cells, encoding for insulin and somatostatin, two pancreatic endocrine products, while repressing glucagon. Thus, Pdx1 expression appearantly favors the production of insulin⁺ β-cells and somatostatin⁺Δ-cells rather than glucagon⁺ α-cells.

Transcriptional Network

Pdx1⁺ pancreatic progenitor cells also co-express Hlxb9, Hnf6, Ptf1a and Nkx6-1, and these progenitor cells form the initial pancreatic buds, which further proliferate and branch in response to FGF-10 signaling. Afterwards, fating 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. Other cells will give rise to the exocrine and ductal pancreatic cell populations.

Pathology

Mutations in the "Pdx1" gene may be involved in several pancreatic pathologies, possibly diabetes mellitus.cite web | title = Entrez Gene: PDX1 pancreatic and duodenal homeobox 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3651| accessdate = ]

References

Further reading

*PBB_Further_reading
citations =
*cite journal | author=Hui H, Perfetti R |title=Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. |journal=Eur. J. Endocrinol. |volume=146 |issue= 2 |pages= 129–41 |year= 2002 |pmid= 11834421 |doi=
*cite journal | author=Leonard J, Peers B, Johnson T, "et al." |title=Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. |journal=Mol. Endocrinol. |volume=7 |issue= 10 |pages= 1275–83 |year= 1994 |pmid= 7505393 |doi=
*cite journal | author=Stoffel M, Stein R, Wright CV, "et al." |title=Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1. |journal=Genomics |volume=28 |issue= 1 |pages= 125–6 |year= 1995 |pmid= 7590740 |doi=
*cite journal | author=Inoue H, Riggs AC, Tanizawa Y, "et al." |title=Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene. |journal=Diabetes |volume=45 |issue= 6 |pages= 789–94 |year= 1996 |pmid= 8635654 |doi=
*cite journal | author=Waeber G, Thompson N, Nicod P, Bonny C |title=Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor. |journal=Mol. Endocrinol. |volume=10 |issue= 11 |pages= 1327–34 |year= 1997 |pmid= 8923459 |doi=
*cite journal | author=Watada H, Kajimoto Y, Kaneto H, "et al." |title=Involvement of the homeodomain-containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription. |journal=Biochem. Biophys. Res. Commun. |volume=229 |issue= 3 |pages= 746–51 |year= 1997 |pmid= 8954967 |doi=
*cite journal | author=Marshak S, Totary H, Cerasi E, Melloul D |title=Purification of the beta-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue= 26 |pages= 15057–62 |year= 1997 |pmid= 8986763 |doi=
*cite journal | author=Stoffers DA, Zinkin NT, Stanojevic V, "et al." |title=Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. |journal=Nat. Genet. |volume=15 |issue= 1 |pages= 106–10 |year= 1997 |pmid= 8988180 |doi= 10.1038/ng0197-106
*cite journal | author=Sharma S, Jhala US, Johnson T, "et al." |title=Hormonal regulation of an islet-specific enhancer in the pancreatic homeobox gene STF-1. |journal=Mol. Cell. Biol. |volume=17 |issue= 5 |pages= 2598–604 |year= 1997 |pmid= 9111329 |doi=
*cite journal | author=Carty MD, Lillquist JS, Peshavaria M, "et al." |title=Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells. |journal=J. Biol. Chem. |volume=272 |issue= 18 |pages= 11986–93 |year= 1997 |pmid= 9115263 |doi=
*cite journal | author=Macfarlane WM, Smith SB, James RF, "et al." |title=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. |journal=J. Biol. Chem. |volume=272 |issue= 33 |pages= 20936–44 |year= 1997 |pmid= 9252422 |doi=
*cite journal | author=Macfarlane WM, Frayling TM, Ellard S, "et al." |title=Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. |journal=J. Clin. Invest. |volume=104 |issue= 9 |pages= R33–9 |year= 1999 |pmid= 10545530 |doi=
*cite journal | author=Hani EH, Stoffers DA, Chèvre JC, "et al." |title=Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. |journal=J. Clin. Invest. |volume=104 |issue= 9 |pages= R41–8 |year= 1999 |pmid= 10545531 |doi=
*cite journal | author=Glick E, Leshkowitz D, Walker MD |title=Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter. |journal=J. Biol. Chem. |volume=275 |issue= 3 |pages= 2199–204 |year= 2000 |pmid= 10636926 |doi=
*cite journal | author=Schwartz PT, Perez-Villamil B, Rivera A, "et al." |title=Pancreatic homeodomain transcription factor IDX1/IPF1 expressed in developing brain regulates somatostatin gene transcription in embryonic neural cells. |journal=J. Biol. Chem. |volume=275 |issue= 25 |pages= 19106–14 |year= 2000 |pmid= 10751390 |doi= 10.1074/jbc.M000655200
*cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=
*cite journal | author=Liu Y, MacDonald RJ, Swift GH |title=DNA binding and transcriptional activation by a PDX1.PBX1b.MEIS2b trimer and cooperation with a pancreas-specific basic helix-loop-helix complex. |journal=J. Biol. Chem. |volume=276 |issue= 21 |pages= 17985–93 |year= 2001 |pmid= 11279116 |doi= 10.1074/jbc.M100678200
*cite journal | author=Samaras SE, Cissell MA, Gerrish K, "et al." |title=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. |journal=Mol. Cell. Biol. |volume=22 |issue= 13 |pages= 4702–13 |year= 2002 |pmid= 12052878 |doi=
*cite journal | author=Zhou J, Pineyro MA, Wang X, "et al." |title=Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. |journal=J. Cell. Physiol. |volume=192 |issue= 3 |pages= 304–14 |year= 2002 |pmid= 12124776 |doi= 10.1002/jcp.10143

External links

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