Biology:PDX1

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Short description: A protein involved in the pancreas and duodenum differentiation


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

PDX1 (pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster.[1] 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.[2][3] The gene was originally identified in the clawed frog Xenopus laevis [4] and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes.[1] Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals.[5] Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.[6]

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.[7] 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.[8] Homozygous Pdx1 knockout mice form pancreatic buds but fail to develop a pancreas,[9] 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.[8]

Pdx1 is accepted as the earliest marker for pancreatic differentiation, with the fates of pancreatic cells controlled by downstream transcription factors.[9] 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.[8] 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.[7] 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.[10]

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,[11] 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.[12][13]

Duodenum

Pdx1 is necessary for the development of the proximal duodenum and maintenance of the gastro-duodenal junction.[14] 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.[14] In mature mice duodenum, several genes have been identified which are dependent on Pdx1 expression and include some affecting lipid and iron absorption.[15]

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.[16] Furthermore, expression of Pdx1 is lost in gastric cancers, suggesting a role for the gene as a tumor suppressor.[17] Maturity onset diabetes of the young (Type 4) can be caused by heterozygous mutations in Pdx1.[18][19] 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.[20]

Interactions

Pdx1 has been shown to interact with MAFA.[21]

References

  1. ↑ 1.0 1.1 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.
  2. ↑ "PDX1". https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=6107. 
  3. ↑ "Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1". Genomics 28 (1): 125–6. July 1995. doi:10.1006/geno.1995.1120. PMID 7590740. 
  4. ↑ 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.
  5. ↑ "OrthoMaM phylogenetic marker: PDX1 coding sequence". 2019. http://www.orthomam.univ-montp2.fr/orthomam_v10b/cds/GenerateDetailMarkers/ENSG00000139515_PDX1.html. 
  6. ↑ "Parallel retention of Pdx2 genes in cartilaginous fish and coelacanths". Molecular Biology and Evolution 27 (10): 2386–91. October 2010. doi:10.1093/molbev/msq121. PMID 20463047. 
  7. ↑ 7.0 7.1 "Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells". Nat. Biotechnol. 24 (11): 1392–401. November 2006. doi:10.1038/nbt1259. PMID 17053790. 
  8. ↑ 8.0 8.1 8.2 "Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver". Nature 445 (7130): 886–91. February 2007. doi:10.1038/nature05537. PMID 17259975. Bibcode: 2007Natur.445..886S. 
  9. ↑ 9.0 9.1 "PAX4 enhances beta-cell differentiation of human embryonic stem cells". PLOS ONE 3 (3): e1783. 2008. doi:10.1371/journal.pone.0001783. PMID 18335054. Bibcode: 2008PLoSO...3.1783L.  open access
  10. ↑ 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
  11. ↑ 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.
  12. ↑ "Increased islet apoptosis in Pdx1+/- mice". J. Clin. Invest. 111 (8): 1147–60. April 2003. doi:10.1172/JCI16537. PMID 12697734. 
  13. ↑ "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. December 2006. doi:10.1073/pnas.0604208103. PMID 17158802. Bibcode: 2006PNAS..10319575J. 
  14. ↑ 14.0 14.1 "The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut". Int. J. Dev. Biol. 57 (5): 391–8. 2013. doi:10.1387/ijdb.120048ah. PMID 23873371. http://www.ijdb.ehu.es/web/descarga/paper/120048ah. 
  15. ↑ "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. 2012. doi:10.1152/ajpgi.00314.2011. PMID 22135308. 
  16. ↑ Fujimoto, Kei, and Kenneth S. Polonsky. "Pdx1 and other factors that regulate pancreatic β‐cell survival." Diabetes, Obesity and Metabolism 11 (2009): 30-37.
  17. ↑ "Pancreatic duodenal homeobox-1 (PDX1) functions as a tumor suppressor in gastric cancer". Carcinogenesis 29 (7): 1327–33. 2008. doi:10.1093/carcin/bgn112. PMID 18477649. 
  18. ↑ "Entrez Gene: PDX1 pancreatic and duodenal homeobox 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3651. 
  19. ↑ "Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young". N. Engl. J. Med. 345 (13): 971–80. September 2001. doi:10.1056/NEJMra002168. PMID 11575290. 
  20. ↑ "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. July 2017. doi:10.1073/pnas.1702930114. PMID 28674003. Bibcode: 2017PNAS..114.7677H. 
  21. ↑ "The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription". J. Biol. Chem. 280 (12): 11887–94. March 2005. doi:10.1074/jbc.M409475200. PMID 15665000. 

Further reading

External links

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



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