Disease relevance of Neurog3

• In addition, ngn3(-/-) mice display intestinal metaplasia of the gastric epithelium [1].
• We delivered Pdx-1 and Ngn3 to the livers of diabetic mice using adeno-associated virus (AAV) serotype 8, a vector that has been shown to result in non-toxic, persistent, high level expression of the transgene [2].
• We were unable to correct hyperglycemia in mice with streptozotocin-induced diabetes using AAV vectors expressing Pdx-1 and Ngn3 [2].

High impact information on Neurog3

• Biliary epithelium in Hes1-/- mice ectopically expresses the proendocrine gene Neurog3 (refs. 12,13), differentiates into endocrine and exocrine cells and forms acini and islet-like structures in the mutant bile ducts [3].
• In these embryos, expression of Isl1 and Atoh5, essential regulators of pancreatic morphogenesis and differentiation, was severely reduced [4].
• These data provide evidence that ngn3 acts as proendocrine gene and that Notch signalling is critical for the decision between the endocrine and progenitor/exocrine fates in the developing pancreas [5].
• One such transcription factor, Arx, exhibits Ngn3-dependent expression throughout endocrine pancreas development in alpha, beta-precursor, and delta cells [6].
• Thus, ngn3 is required for the differentiation of enteroendocrine cells in the stomach and the maintenance of gastric epithelial cell identity [1].

Biological context of Neurog3

• During embryonic development of the pancreas, IA1 and Ngn3 exhibit nearly identical spatio-temporal expression patterns [7].
• Upon ectopic expression in adult pancreatic duct cells Ngn3 binds to chromatin in the IA1 promoter region and activates transcription [7].
• We identify the gene encoding IA1, a zinc-finger transcription factor, as a direct target of Ngn3 and show that it forms a novel branch in the Ngn3-dependent endocrinogenic transcription factor network [7].
• Neurogenin 3 (Ngn3) is key for endocrine cell specification in the embryonic pancreas and induction of a neuroendocrine cell differentiation program by misexpression in adult pancreatic duct cells [7].
• During fetal development, all endocrine cells are derived from Ngn3(+) precursors [8].

Anatomical context of Neurog3

• Neurogenin 3 and the enteroendocrine cell lineage in the adult mouse small intestinal epithelium [9].
• Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity [1].
• Regeneration of pancreatic islets after partial pancreatectomy in mice does not involve the reactivation of neurogenin-3 [8].
• Mice homozygous for a null mutation in ngn3 fail to generate any intestinal endocrine cells, and endocrine progenitor cells are lacking [10].
• Furthermore, overexpression of ngn3 could cause a dose-dependent activation on the 1.0-kb BETA2 promoter in islet-derived cell lines [11].

Associations of Neurog3 with chemical compounds

• PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance [12].
• Furthermore, in streptozotocin-induced diabetic mice, PDX-1/VP16 overexpression, together with NeuroD or Ngn3, drastically ameliorated glucose tolerance [12].

Co-localisations of Neurog3

• Sox3 expression was restricted to proliferating germ cells and colocalized with neurogenin 3 (Ngn3), a helix-loop-helix transcription factor implicated in spermatogonial differentiation [13].

Regulatory relationships of Neurog3

• We show herein that ngn3-positive cells coexpress neither insulin nor glucagon, suggesting that ngn3 marks early precursors of pancreatic endocrine cells [14].
• However, embryos lacking Ngn3 fail to express IA1 in the pancreas [7].
• Furthermore, endocrine differentiation is associated with escape from this activity, because Ngn3-expressing endocrine precursors are susceptible to Notch inhibition, whereas fully differentiated endocrine cells are resistant [15].
• Gdf11 is expressed in embryonic pancreatic epithelium during formation of islet progenitor cells that express neurogenin 3 [16].
• We showed previously that the Onecut transcription factor HNF-6 promotes differentiation of the endocrine cell precursors in which it stimulates expression of the proendocrine gene Ngn-3 [17].

Other interactions of Neurog3

• Following transfection, PDX-1, ngn3, beta 2, and Nkx2.2 were expressed in F9-RAC cells, with their proteins localized mainly in cellular nuclei [18].
• Despite full recovery of beta-cell mass after 50% partial pancreatectomy (Ppx) in BALB/c mice, no pancreatic Ngn3 immunoreactivity was detected, even when the beta-cell trophic glucagon-like peptide-1 receptor agonist exendin-4 was administered after the procedure [8].
• We conclude that Sox3 is expressed in A(s), A(pr) and A(al) spermatogonia and is required for spermatogenesis through a pathway that involves Ngn3 [13].
• We present several observations that collectively indicate that Hnf1beta+ cells are the immediate precursors of Ngn3+ cells [19].
• Deletion and mutation analyses revealed that two proximal E box sequences, E1 and E3, could bind to ngn3-E47 heterodimer and mediate ngn3 activation [11].

Analytical, diagnostic and therapeutic context of Neurog3

• To understand the molecular basis of enteroendocrine cell development, we have used gene targeting in mouse embryonic stem cells to derive an EGFP-marked null allele of the bHLH transcription factor, neurogenin 3 (ngn3) [1].
• The purified (96%) EGFP-expressing cells, which represent 20% of the total cell population, were shown by RT/PCR to express exocrine cell markers (amylase and P48) and endocrine cell markers (insulin 1, insulin 2, and Ngn3) [20].
• Genomic Southern blot hybridization suggested that a closely related sequence is present in the zebrafish genome and the hypothetical gene might result from the recent genome duplication in certain teleost lineage and share the function of the common ancestor with the currently characterized ngn3 [21].
• Using degenerate PCR, the P. obesus Neurogenin-3 (Ngn-3) gene was cloned [22].

References