PDX1
Template:Cs1 config Template:Short description Template:Infobox gene 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
<templatestyles src="Reflist/styles.css" />
- ↑ a b 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.
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ 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.
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b Script error: No such module "Citation/CS1".
- ↑ a b c Script error: No such module "Citation/CS1".
- ↑ a b Script error: No such module "Citation/CS1". Template:Open access
- ↑ 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
- ↑ 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.
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Fujimoto, Kei, and Kenneth S. Polonsky. "Pdx1 and other factors that regulate pancreatic β‐cell survival." Diabetes, Obesity and Metabolism 11 (2009): 30-37.
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
Script error: No such module "Check for unknown parameters".
Further reading
<templatestyles src="Refbegin/styles.css" />
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
- Script error: No such module "Citation/CS1".
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.