Neurogenin-3 (NGN3) is a protein that in humans is encoded by the Neurog3 gene.
Neurogenin-3 is a pro-endocrine transcription factor that is a member of the basic helix-loop-helix (bHLH) transcription factor and has a primary function of activating gene transcription in endocrine progenitor cells. [5] It is a master regulator of pancreatic islet differentiation and regeneration [6] and functions to directly enhance the expression of the lineage-committed transcription factors required for the differentiation of the endocrine progenitor cells into each of the endocrine cell subtypes. [6]
Neurogenin3 is expressed in a small percentage of cells within the developing pancreas consisting of endocrine progenitor cells. [6] It is expressed in the three stages of the development and differentiation of the endocrine pancreas. These stages are termed the
The significance of NGN3 in endocrine cell development is shown by the fact that Neurog3 deficiency prevents the generation of all pancreatic and intestinal endocrine cells( [9] [10] ). Ectopic overexpression of Neurog3 leads to reduced endocrine mass as well, but by a mechanism that is different from that of Neurog3 deficiency. [11] Overexpression of Neurog3 throughout the uncommitted pancreatic progenitor domain induces premature differentiation of the progenitor cell population into the endocrine lineage, effectively depleting the pool of multi-potent progenitor cells prior to their expansion resulting in a reduction in the overall mass of pancreatic endocrine tissue. [6] These data point at a tight regulation of Neurog3 expression to maintain the proper size and cell composition of the endocrine pancreas.
Genetic mutations in Neurogenin3 have been often found to cause neonatal diabetes [12] and the significance of neurogenin3 has also been further shown using invitro analysis where neurogenin3 was found to required for the development of mature human beta cells from pluripotent stem cells. [12]
Neurogenin-3 is required for the development of endocrine pancreatic precursors for the four pancreatic endocrine cell types composed in the Islets of Langerhans: α-, β-, δ-, and pancreatic polypeptide (PP) cells, which produce the hormones glucagon, insulin, somatostatin, and PP respectively. [13]
Neurogenin-3 producing cells are is located within or adjacent to the pancreatic ducts, which are thought to produce endocrine precursors. [14]
In the absence of Neurogenin-3, expression of ISL1, PAX4, PAX6, and NeuroD are lost and endocrine precursors are lacking in the pancreatic epithelium. Neurogenin-3 absence also results in the absence of both insulin and glucagon detected normally at stages E15.5 and E9.5 in mouse embryos. [13]
Tissues lacking Neurogenin-3 result in an abnormal exocrine tissue phenotype nearly identical to that of tissues with the loss of NeuroD expression. [15] This phenotype is composed of abnormal cell polarity with nuclei having random positions and an abundant accumulation of Acinar Cells and Zymogen granules. [13]
Transcription factors control gene expression by interacting with enhancer sequences. The transcription factors pancreas/duodenum homeobox protein 1 (PDX1), Neurogenin-3 (NEUROG3), and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) are required for beta cell growth and differentiation. NEUROG3 governs islet differentiation and restoration and is expressed in endocrine progenitor cells. PDX1 is required for the formation of exocrine and endocrine cells in the pancreas, especially beta cells. PDX1 also attaches to regulatory regions, causing insulin gene transcription to rise. Similarly, MAFA binds to the insulin gene's enhancer/promoter region and stimulates insulin production in response to glucose. PDX1, NEUROG3, and/or MAFA have been effectively used to convert numerous cell types into insulin-producing cells in vitro and in vivo, including pancreatic exocrine cells, hepatocytes, and pluripotent stem cells, in addition to their natural roles in beta cell formation and maturation. In this paper, we look at the biological features of PDX1, NEUROG3, and MAFA, [16] as well as their applications and limitations in beta cell regeneration. A PubMed search for papers published between 1990 and 2017 was used to find the primary source literature for this review. Diabetes, insulin, trans-differentiation, stem cells, and regenerative medicine are all search phrases.
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 hypothalamus is the neural control center for all endocrine systems.
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e., it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins and fats in food entering the duodenum from the stomach.
Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.
Transdifferentiation, also known as lineage reprogramming, is the process in which one mature somatic cell is transformed into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type. It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine. The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis.
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% of the pancreas volume and receive 10–15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.
Alpha cells (α-cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.
Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
Epsilon cells (ε-cells) are one of the five types of endocrine cells found in regions of the pancreas called Islets of Langerhans. Epsilon cells produce the hormone ghrelin that induces hunger. They were first discovered in mice. In humans, these cells compose less than 1% of all islet cells. They are connected by tight junctions that allow impermeability to water-soluble compounds.
PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. 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. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian 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 have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.
Paired box gene 4, also known as PAX4, is a protein which in humans is encoded by the PAX4 gene.
Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the ISL1 gene.
Neurogenins, often abbreviated as Ngn, are a family of bHLH transcription factors involved in specifying neuronal differentiation. The family consisting of Neurogenin-1, Neurogenin-2, and Neurogenin-3, plays a fundamental role in specifying neural precursor cells and regulating the differentiation of neurons during embryonic development. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.
Pancreas transcription factor 1 subunit alpha is a protein that in humans is encoded by the PTF1A gene.
Transcription factor MafA is a protein that in humans is encoded by the MAFA gene. It is a member of the Maf family of transcription factors.
Renal cysts and diabetes syndrome (RCAD), also known as MODY 5 or HNF1B-MODY, is a form of maturity onset diabetes of the young.
Homeobox protein Nkx-6.1 is a protein that in humans is encoded by the NKX6-1 gene.
Ductal cells refer to the epithelial cell lining of the pancreatic duct that deliver enzymes from the acinar cells to the duodenum. They have the essential function of producing bicarbonate-rich (HCO3-) secretion to neutralize stomach acidity. The hormone secretin stimulates ductal cells and is responsible for maintaining the duodenal pH and preventing duodenal injury from acidic chyme. Ductal cells mix their production with acinar cells to make up the pancreatic juice.
Regulatory factor X, 6 also known as DNA-binding protein RFX6 is a protein that in humans is encoded by the RFX6 gene.
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.
Islet resident macrophages are the predominant myeloid cell of the pancreatic islets of langerhans.