PDX1

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Pancreatic and duodenal homeobox 1
Protein PDX1 PDB 2h1k.png
PDB rendering based on 2h1k.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PDX1 ; GSF; IDX-1; IPF1; IUF1; MODY4; PDX-1; STF-1
External IDs OMIM600733 MGI102851 HomoloGene175 GeneCards: PDX1 Gene
RNA expression pattern
PBB GE PDX1 210938 at tn.png
PBB GE PDX1 210937 s at tn.png
More reference expression data
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:
28.49 – 28.5 Mb
Chr 5:
147.27 – 147.28 Mb
PubMed search [1] [2]

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 (in rodents), otherwise known as Ipf1 (in humans), is the gene encoding it.[1]

Function[edit]

Pancreatic development[edit]

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.[2] 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,[3] 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.[4] Homozygous Pdx1 knockout mice form pancreatic buds but fail to develop a pancreas,[4] 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.[3]

β-cell maturation and survival[edit]

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.[2] 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 apparently favors the production of insulin+ β-cells and somatostatin+Δ-cells rather than glucagon+ α-cells. In addition to roles in beta-cell differentiation, Pdx1 is required for β-cell survival. Cells with reduced Pdx1 have an increased rate of apoptotic programmed cell death.[5][6]

Transcriptional Network[edit]

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.[3] Other cells will give rise to the exocrine and ductal pancreatic cell populations.

Pathology[edit]

Mutations in the Pdx1 gene may be involved in several pancreatic pathologies, including diabetes mellitus. Maturity onset diabetes of the young (Type 4) can be caused by heterozygous mutations in Pdx1 [7][8]

Interactions[edit]

Pdx1 has been shown to interact with MAFA.[9]

References[edit]

  1. ^ 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. 
  2. ^ a b 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. 
  3. ^ a b c 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. doi:10.1038/nature05537. PMID 17259975. 
  4. ^ a b 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. doi:10.1371/journal.pone.0001783. PMC 2262135. PMID 18335054. 
  5. ^ 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. 
  6. ^ 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. doi:10.1073/pnas.0604208103. PMC 1748267. PMID 17158802. 
  7. ^ "Entrez Gene: PDX1 pancreatic and duodenal homeobox 1". 
  8. ^ 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. 
  9. ^ 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[edit]

External links[edit]

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