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Results: 21 to 27 of 27

Publication Record


Neurogenin 3 and the enteroendocrine cell lineage in the adult mouse small intestinal epithelium.
Bjerknes M, Cheng H
(2006) Dev Biol 300: 722-35
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Clone Cells, Enteroendocrine Cells, Intestinal Mucosa, Intestine, Small, Male, Mice, Nerve Tissue Proteins
Show Abstract · Added July 30, 2010
It is thought that small intestinal epithelial stem cell progeny, via Notch signaling, yield a Hes1-expressing columnar lineage progenitor and an Atoh1 (also known as Math1)-expressing common progenitor for all granulocytic lineages including enteroendocrine cells, one of the body's largest populations of endocrine cells. Because Neurogenin 3 (Neurog3) null mice lack enteroendocrine cells, Neurog3-expressing progenitors derived from the common granulocytic progenitor are thought to produce the enteroendocrine lineage, although more recent work indicates that Neurog3+ progenitors also contribute to non-enteroendocrine lineages. We aimed to test this model and better characterize the progenitors leading from the stem cells to the enteroendocrine lineage. We investigated clones derived from enteroendocrine precursors and found no evidence of a common granulocytic progenitor that routinely yields all granulocytic lineages. Rather, enteroendocrine cells are derived from a short-lived bipotential progenitor whose offspring, probably via Notch signaling, yield a Neurog3+ cell committed to the enteroendocrine lineage and a progenitor committed to the columnar lineage. The Neurog3+ cell population is heterogeneous; only about 1/3 are slowly cycling progenitors, the rest are postmitotic cells in early stages of enteroendocrine differentiation. No evidence was found that Neurog3+ cells contribute to non-enteroendocrine lineages. Revised lineage models for the small intestinal epithelium are introduced.
0 Communities
0 Members
2 Resources
11 MeSH Terms
Complementation rescue of Pdx1 null phenotype demonstrates distinct roles of proximal and distal cis-regulatory sequences in pancreatic and duodenal expression.
Boyer DF, Fujitani Y, Gannon M, Powers AC, Stein RW, Wright CV
(2006) Dev Biol 298: 616-31
MeSH Terms: Animals, Cell Differentiation, Duodenum, Enteroendocrine Cells, Gastric Mucosa, Gene Dosage, Gene Expression, Genetic Complementation Test, Glucose Intolerance, Homeodomain Proteins, Mice, Mice, Knockout, Models, Biological, Pancreas, Phenotype, Regulatory Elements, Transcriptional, Trans-Activators
Show Abstract · Added January 6, 2014
The unique, well-demarcated expression domain of Pdx1 within the posterior foregut suggests that investigating its transcriptional regulation will provide insight into mechanisms that regionally pattern the endoderm. Previous phylogenetic comparison identified conserved noncoding regions that stimulate transcriptional activity selectively in cultured pancreatic beta cells. Characterization of these regulatory elements is helping to dissect the transcription factor networks that operate within beta cells, which is important for understanding the etiology of beta cell dysfunction and diabetes, as well as for developing methods to produce beta cells in vitro for cell-based therapies. We recently reported that deletion of three proximally located conserved areas (Area I-II-III) from the endogenous Pdx1 locus resulted in severely reduced expression of Pdx1 in the pancreas, and a milder decrease in other foregut tissues. Here, we report transgene-based complementation experiments on Pdx1 null mice, which reveal that the proximal promoter/enhancer region, including Area I-II-III, rescues the pancreatic defects caused by Pdx1 deficiency, but only weakly promotes expression of Pdx1 in the postnatal stomach and duodenum. These results reveal a role for distal cis-regulatory elements in achieving the correct level of extra-pancreatic Pdx1 expression, which is necessary for the production of duodenal GIP cells and stomach gastrin cells.
3 Communities
3 Members
0 Resources
17 MeSH Terms
The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells.
Gierl MS, Karoulias N, Wende H, Strehle M, Birchmeier C
(2006) Genes Dev 20: 2465-78
MeSH Terms: Animals, Cell Differentiation, DNA-Binding Proteins, Enteroendocrine Cells, Female, Gene Expression Regulation, Developmental, Humans, Insulin-Secreting Cells, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Transcription Factors, Zinc Fingers
Show Abstract · Added June 10, 2010
The pancreatic and intestinal primordia contain epithelial progenitor cells that generate many cell types. During development, specific programs of gene expression restrict the developmental potential of such progenitors and promote their differentiation. The Insm1 (insulinoma-associated 1, IA-1) gene encodes a Zinc-finger factor that was discovered in an insulinoma cDNA library. We show that pancreatic and intestinal endocrine cells express Insm1 and require Insm1 for their development. In the pancreas of Insm1 mutant mice, endocrine precursors are formed, but only few insulin-positive beta cells are generated. Instead, endocrine precursor cells accumulate that express none of the pancreatic hormones. A similar change is observed in the development of intestine, where endocrine precursor cells are formed but do not differentiate correctly. A hallmark of endocrine cell differentiation is the accumulation of proteins that participate in secretion and vesicle transport, and we find many of the corresponding genes to be down-regulated in Insm1 mutant mice. Insm1 thus controls a gene expression program that comprises hormones and proteins of the secretory machinery. Our genetic analysis has revealed a key role of Insm1 in differentiation of pancreatic and intestinal endocrine cells.
1 Communities
0 Members
1 Resources
16 MeSH Terms
Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation.
Fujitani Y, Fujitani S, Boyer DF, Gannon M, Kawaguchi Y, Ray M, Shiota M, Stein RW, Magnuson MA, Wright CV
(2006) Genes Dev 20: 253-66
MeSH Terms: Animals, Cell Differentiation, Conserved Sequence, Diabetes Mellitus, Type 2, Enteroendocrine Cells, Female, Gene Expression Regulation, Developmental, Homeodomain Proteins, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Organogenesis, Pancreas, Regulatory Sequences, Nucleic Acid, Trans-Activators
Show Abstract · Added December 10, 2013
Pdx1 (IPF-1 in humans, which is altered in MODY-4) is essential for pancreas development and mature beta-cell function. Pdx1 is expressed dynamically within the developing foregut, but how its expression characteristics are linked to the various steps of organ specification, differentiation, and function is unknown. Deletion of a conserved enhancer region (Area I-II-III) from Pdx1 produced a hypomorphic allele (Pdx1(DeltaI-II-III)) with altered timing and level of expression, which was studied in combination with wild-type and protein-null alleles. Lineage labeling in homozygous Area I-II-III deletion mutants (Pdx1(DeltaI-II-III/DeltaI-II-III)) revealed lack of ventral pancreatic bud specification and early-onset hypoplasia in the dorsal bud. Acinar tissue formed in the hypoplastic dorsal bud, but endocrine maturation was greatly impaired. While Pdx1(-/-) (protein-null) mice have nonpancreatic abnormalities (e.g., distorted pylorus, absent Brunner's glands), these structures formed normally in Pdx1(DeltaI-II-III/DeltaI-II-III) and Pdx1(DeltaI-II-III/-) mice. Surprisingly, heterozygous (Pdx1(+/DeltaI-II-III)) mice had abnormal islets and a more severe prediabetic condition than Pdx1(+/-) mice. These findings provide in vivo evidence of the differential requirements for the level of Pdx1 gene activity in the specification and differentiation of the various organs of the posterior foregut, as well as in pancreas and gut endocrine cell differentiation.
3 Communities
5 Members
0 Resources
18 MeSH Terms
Mtgr1 is a transcriptional corepressor that is required for maintenance of the secretory cell lineage in the small intestine.
Amann JM, Chyla BJ, Ellis TC, Martinez A, Moore AC, Franklin JL, McGhee L, Meyers S, Ohm JE, Luce KS, Ouelette AJ, Washington MK, Thompson MA, King D, Gautam S, Coffey RJ, Whitehead RH, Hiebert SW
(2005) Mol Cell Biol 25: 9576-85
MeSH Terms: Animals, Cell Line, Cell Lineage, Cercopithecus aethiops, Enteroendocrine Cells, Goblet Cells, Histone Deacetylases, Humans, Intestine, Small, Mice, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Paneth Cells, Phosphoproteins, Protein Binding, Repressor Proteins, Transcription, Genetic
Show Abstract · Added August 13, 2010
Two members of the MTG/ETO family of transcriptional corepressors, MTG8 and MTG16, are disrupted by chromosomal translocations in up to 15% of acute myeloid leukemia cases. The third family member, MTGR1, was identified as a factor that associates with the t(8;21) fusion protein RUNX1-MTG8. We demonstrate that Mtgr1 associates with mSin3A, N-CoR, and histone deacetylase 3 and that when tethered to DNA, Mtgr1 represses transcription, suggesting that Mtgr1 also acts as a transcriptional corepressor. To define the biological function of Mtgr1, we created Mtgr1-null mice. These mice are proportionally smaller than their littermates during embryogenesis and throughout their life span but otherwise develop normally. However, these mice display a progressive reduction in the secretory epithelial cell lineage in the small intestine. This is not due to the loss of small intestinal progenitor cells expressing Gfi1, which is required for the formation of goblet and Paneth cells, implying that loss of Mtgr1 impairs the maturation of secretory cells in the small intestine.
2 Communities
4 Members
0 Resources
17 MeSH Terms
Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium.
Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M, Gradwohl G
(2002) EMBO J 21: 6338-47
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Enteroendocrine Cells, Epithelium, Intestinal Mucosa, Intestines, Mice, Mice, Transgenic, Nerve Tissue Proteins, Promoter Regions, Genetic
Show Abstract · Added July 7, 2015
Endocrine cells of the pancreas and the gastrointestinal tract derive from multipotent endodermal stem cells. We have shown previously that the basic helix- loop-helix (bHLH) transcription factor neurogenin3 (ngn3) is required for the specification of the endocrine lineage in uncommitted progenitors in the developing pancreas. We investigate herein the expression and the function of ngn3 in the control of endocrine cell development in the intestinal and gastric epithelium. Our results indicate that as in the pancreas, gastrointestinal endocrine cells derive from ngn3-expressing progenitors. Mice homozygous for a null mutation in ngn3 fail to generate any intestinal endocrine cells, and endocrine progenitor cells are lacking. The other main intestinal epithelial cell types differentiate properly. In contrast, in the glandular stomach, the differentiation of the gastrin- (G cells) and somatostatin (D cells)-secreting cells is impaired whereas serotonin- (enterochromaffin EC cells), histamine- (enterochromaffin-like ECL cells) and ghrelin (X/A cells)-expressing cells are still present. Thus, ngn3 is strictly required for endocrine cell fate specification in multipotent intestinal progenitor cells, whereas gastric endocrine development is both ngn3 dependent and independent.
0 Communities
0 Members
0 Resources
11 MeSH Terms
Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity.
Lee CS, Perreault N, Brestelli JE, Kaestner KH
(2002) Genes Dev 16: 1488-97
MeSH Terms: Alleles, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Division, Cell Lineage, DNA-Binding Proteins, Digestive System, Enterochromaffin Cells, Enteroendocrine Cells, Epithelial Cells, Gastric Mucosa, Gastrins, Gene Expression Regulation, Developmental, Glucagon, Green Fluorescent Proteins, Immunohistochemistry, Luminescent Proteins, Mice, Mice, Inbred C57BL, Microscopy, Electron, Microscopy, Fluorescence, Models, Genetic, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, RNA, RNA, Messenger, Signal Transduction, Somatostatin, Stomach, Transcription Factors
Show Abstract · Added July 7, 2015
The notch signaling pathway is essential for the endocrine cell fate in various tissues including the enteroendocrine system of the gastrointestinal tract. Enteroendocrine cells are one of the four major cell types found in the gastric epithelium of the glandular stomach. 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). In ngn3(-/-) mice, glucagon secreting A-cells, somatostatin secreting D-cells, and gastrin secreting G-cells are absent from the epithelium of the glandular stomach, whereas the number of serotonin-expressing enterochromaffin (EC) cells is decreased dramatically. In addition, ngn3(-/-) mice display intestinal metaplasia of the gastric epithelium. Thus, ngn3 is required for the differentiation of enteroendocrine cells in the stomach and the maintenance of gastric epithelial cell identity.
0 Communities
0 Members
0 Resources
31 MeSH Terms