PDX1 (pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
in the
ParaHox gene cluster.
[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.] In vertebrates, Pdx1 is necessary for
pancreatic development, including
β-cell maturation, and
duodenal differentiation. In humans this
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
is encoded by the ''PDX1'' gene, which was formerly known as ''IPF1''.
The gene was originally identified in the clawed frog ''
Xenopus laevis
The African clawed frog (''Xenopus laevis''), also known as simply xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the short black ...
'' and is present widely across the evolutionary diversity of
bilaterian
Bilateria () is a large clade of animals characterised by bilateral symmetry during embryonic development. This means their body plans are laid around a longitudinal axis with a front (or "head") and a rear (or "tail") end, as well as a left–r ...
animals, although it has been lost in evolution in arthropods and nematodes.
[ Despite the gene name being ''Pdx1'', there is no ''Pdx2'' gene in most animals; single-copy Pdx1 ]orthologs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
have been identified in all mammals
A mammal () is a vertebrate animal of the class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three middle e ...
. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two ''Pdx'' genes, ''Pdx1'' and ''Pdx2''.
Function
Pancreatic development
In pancreatic development, Pdx1 is expressed by a population of cells in the posterior foregut
The foregut in humans is the anterior part of the alimentary canal, from the distal esophagus to the first half of the duodenum, at the entrance of the bile duct. Beyond the stomach, the foregut is attached to the abdominal walls by mesentery. ...
region of the definitive endoderm, and Pdx1+ epithelial cells
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
give rise to the developing pancreatic bud
The ventral and dorsal pancreatic buds (or pancreatic diverticula) are outgrowths of the duodenum during human embryogenesis. They join to form the adult pancreas.
The proximal portion of the dorsal pancreatic bud gives rise to the accessory panc ...
s, and eventually, the whole of the pancreas—its exocrine, endocrine, and ductal cell populations. 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. Homozygous ''Pdx1'' knockout mice form pancreatic buds but fail to develop a pancreas,[ and transgenic mice in which ]tetracycline
Tetracycline, sold under various brand names, is an antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. It is available in oral an ...
application results in death of Pdx1+ cells are almost completely apancreatic if doxycycline
Doxycycline is a Broad-spectrum antibiotic, broad-spectrum antibiotic of the Tetracycline antibiotics, tetracycline class used in the treatment of infections caused by bacteria and certain parasites. It is used to treat pneumonia, bacterial p ...
(tetracycline derivative) is administered throughout the pregnancy of these transgenic mice, illustrating the necessity of Pdx1+ cells in pancreatic development.[
Pdx1 is accepted as the earliest marker for pancreatic differentiation, with the fates of pancreatic cells controlled by downstream transcription factors.][ ] The initial pancreatic bud is composed of Pdx1+ pancreatic progenitor cell
Pancreatic progenitor cells are multipotent stem cells originating from the developing fore-gut endoderm which have the ability to differentiate into the lineage specific progenitors responsible for the developing pancreas.
They give rise to bot ...
s that co-express Hlxb9, Hnf6, Ptf1a
Pancreas transcription factor 1 subunit alpha is a protein that in humans is encoded by the ''PTF1A'' gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucle ...
and NKX6-1. These cells further proliferate and branch in response to FGF-10
Fibroblast growth factor 10 is a protein that in humans is encoded by the ''FGF10'' gene. It is a polypeptide of 208 amino acids. Human FGF10 gene is highly homologous (95.6%) to rat FGF10, where it was first discovered.
Function
The protein ...
signaling. Afterwards, differentiation of the pancreatic cells begins; a population of cells has Notch signaling
The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transme ...
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
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% o ...
.[ Other cells will give rise to the ]exocrine
Exocrine glands are glands that secrete substances onto an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of t ...
and ductal pancreatic cell populations.
β-cell maturation and survival
The final stages of pancreas development involves the production of different endocrine
The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
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
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
, a process that results in the silencing of MafB and the expression of MafA, a necessary switch in maturation of β-cells. 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.[ 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]
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,[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.] 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.
Duodenum
Pdx1 is necessary for the development of the proximal duodenum and maintenance of the gastro-duodenal junction. Duodenal enterocytes
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase i ...
, Brunner's glands
Brunner's glands (or duodenal glands) are compound tubuloalveolar submucosal glands found in that portion of the duodenum proximal to the hepatopancreatic sphincter (i.e sphincter of Oddi).
For decades, it was believed that the main function of ...
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. In mature mice duodenum, several genes have been identified which are dependent on Pdx1 expression and include some affecting lipid and iron absorption.
Pathology
Experiments in animal models have shown that a reduction in Pdx1 expression can cause symptoms that are characteristic of Diabetes mellitus type 1
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone required ...
and Diabetes mellitus type 2
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
.[Fujimoto, Kei, and Kenneth S. Polonsky. "Pdx1 and other factors that regulate pancreatic β‐cell survival." Diabetes, Obesity and Metabolism 11 (2009): 30-37.] Furthermore, expression of Pdx1 is lost in gastric cancers, suggesting a role for the gene as a tumor suppressor. Maturity onset diabetes of the young (Type 4) can be caused by heterozygous mutations in Pdx1. The fat sand rat '' Psammomys obesus'', a species with susceptibility to Diabetes mellitus type 2
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
symptoms, has a highly divergent ''Pdx1'' gene sequence compared with other mammals.
Interactions
Pdx1 has been shown to interact with MAFA.
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Permanent Neonatal Diabetes Mellitus
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{{Transcription factors, g3
Transcription factors