Expression of peptide YY in all four islet cell types in the developing mouse pancreas suggests a common peptide YY-producing progenitor

Development ◽  
1994 ◽  
Vol 120 (2) ◽  
pp. 245-252 ◽  
Author(s):  
B.H. Upchurch ◽  
G.W. Aponte ◽  
A.B. Leiter
Keyword(s):  
Transgenic Mice ◽  
Pancreatic Polypeptide ◽  
Islet Cell ◽  
Endocrine Cells ◽  
Peptide Yy ◽  
Cell Types ◽  
T Antigen ◽  
Cell Lineages ◽  
Pancreatic Polypeptide Cells ◽  
Islet Cell Types

The islets of Langerhans contain four distinct endocrine cell types producing the hormones glucagon, insulin, somatostatin and pancreatic polypeptide. These cell lineages are thought to arise from a common, multipotential progenitor cell whose identity has not been well established. The pancreatic and intestinal hormone, peptide YY, has been previously identified in glucagon-producing cells in islets; however, transgenic mice expressing Simian Virus 40 large T antigen under the control of the peptide YY gene expressed the oncoprotein in beta, delta and pancreatic polypeptide cells, and occasionally developed insulinomas, suggesting relationships between peptide YY-producing cells and several islet cell lineages. The four established pancreatic islet cell types were examined for coexpression of peptide YY in islets of normal and transgenic mice throughout development. Peptide YY immunoreactivity was identified in the earliest endocrine cells in the fetal pancreas and was coexpressed in each islet cell type during development. Peptide YY showed a high degree of co-localization with glucagon- and insulin-producing cells in early pancreatic development, but by adulthood, peptide YY was expressed in less than half of the alpha cells and was no longer expressed in beta cells. Peptide YY was also coexpressed with somatostatin and pancreatic polypeptide when these cell types first appeared, but most delta and pancreatic polypeptide cells continued to express peptide YY throughout development. The use of conditions that distinguish peptide YY from the related peptides, pancreatic polypeptide and neuropeptide Y, as well as the ability of the peptide YY gene to direct expression of a reporter gene in islets of transgenic mice, establishes expression of peptide YY in the earliest pancreatic endocrine cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Peptide YY expression is an early event in colonic endocrine cell differentiation: evidence from normal and transgenic mice

Development ◽  
1996 ◽  
Vol 122 (4) ◽  
pp. 1157-1163 ◽  
Author(s):  
B.H. Upchurch ◽  
B.P. Fung ◽  
G. Rindi ◽  
A. Ronco ◽  
A.B. Leiter
Keyword(s):  
Substance P ◽  
Transgenic Mice ◽  
Endocrine Cells ◽  
Peptide Yy ◽  
Simian Virus 40 ◽  
Cell Types ◽  
T Antigen ◽  
Early Event ◽  
Endocrine Tumors ◽  
Endocrine Differentiation

The hormone peptide YY is produced by endocrine cells in the pancreas, ileum and colon. We have previously shown that peptide YY is coexpressed in all four islet cell types in the murine pancreas when they first appear, suggesting a common peptide YY-producing progenitor. In the colon, peptide YY has been frequently identified in glucagon-expressing L-type endocrine cells. Characterization of colonic endocrine tumors in transgenic mice expressing simian virus 40 large T antigen under the control of the peptide YY gene 5′ flanking region revealed tumor cells producing not only peptide YY and glucagon, but also neurotensin, cholecystokinin, substance P, serotonin, secretin, and gastrin. This suggested that multiple enteroendocrine lineages were related to peptide YY-producing cells. Subsequent examination of the ontogeny of colonic endocrine differentiation in nontransgenic mice revealed that peptide YY was the first hormone to appear during development, at embryonic day 15.5. Between embryonic days 16.5 and 18.5, cells expressing glucagon, cholecystokinin, substance P, serotonin, secretin, neurotensin, gastrin and somatostatin first appeared and peptide YY was coexpressed in each cell type at this time. Peptide YY coexpression continued in a significant fraction of most enteroendocrine cell types throughout fetal and postnatal development and into adulthood, with the exception of serotonin-producing cells. This latter population of cells expanded dramatically after birth with rare coexpression of peptide YY. These studies indicate that expression of peptide YY is an early event in colonic endocrine differentiation and support the existence of a common progenitor for all endocrine cells in the colon.

Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide

Development ◽  
1993 ◽  
Vol 118 (4) ◽  
pp. 1031-1039 ◽  
Author(s):  
G. Teitelman ◽  
S. Alpert ◽  
J.M. Polak ◽  
A. Martinez ◽  
D. Hanahan
Keyword(s):  
Neuropeptide Y ◽  
Progenitor Cells ◽  
Pancreatic Polypeptide ◽  
Islet Cell ◽  
Endocrine Pancreas ◽  
Cell Types ◽  
Cross Reactivity ◽  
Precursor Cells ◽  
Electron Microscopic ◽  
Islet Cell Types

The early progenitor cells to the pancreatic islets in the mouse have been characterized so as to re-examine their possible lineage relationships to the four islet cell types found in mature islets. Insulin and glucagon were both first expressed at embryonic day 9.5, and many cells coexpressed these two markers, as shown by light and electron microscopic analysis using double-label immunohistochemistry. Incubation of embryonic pancreas with 1% glutaraldehyde, a fixative commonly used by electron microscopists, abolished this reactivity, thereby explaining reported difficulties in detecting these precursor cells. Using antisera specific for neuropeptide Y (NPY) a peptide with considerable homology to pancreatic polypeptide (PP), we show that NPY first appears with insulin and glucagon immunoreactivity at E9.5, and is co-expressed with glucagon in a majority of adult alpha cells. As we have previously reported, PP itself is first detectable immunocytochemically at postnatal day 1 with PP-specific antibodies. However, antibodies raised against bovine PP are shown by dot blotting to recognize NPY with comparable avidity, indicating that a recent report of islet progenitor cells containing PP at E9.5 (Herrera, P. L., Huarte, J., Sanvito, F., Meda, P., Orci, L. and Vassalli, J. D. (1991) Development 113, 1257–1265), actually represents cross-reactivity to NPY. The data support a model in which early precursor cells to the endocrine pancreas co-activate and co-express a set of islet cell hormone and neural genes, whose expression is both selectively increased and extinguished as development proceeds, concomitant with a restriction to the patterns of expression characteristic of mature islet cell types.

Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice

Development ◽  
1993 ◽  
Vol 118 (1) ◽  
pp. 33-46 ◽  
Author(s):  
D. Gu ◽  
N. Sarvetnick
Keyword(s):  
Transgenic Mice ◽  
Islet Cell ◽  
Endocrine Cells ◽  
Islet Cells ◽  
Cell Types ◽  
Model System ◽  
Epithelial Cell Proliferation ◽  
Islet Neogenesis ◽  
Islet Development ◽  
Duct Cells

We have identified a model system for the study of pancreatic islet development and regeneration in transgenic mice bearing the interferon-gamma (IFN-g) gene expressed in the pancreatic islets. Previous studies showed that the locally produced IFN-g causes lymphocyte infiltration and islet cell destruction. Here we demonstrate that new islet cells are formed continuously from duct cells as evidenced by (1) the dramatic proliferation of duct cells, (2) the appearance of primitive cells and (3) their subsequent differentiation to endocrine cells. The IFN-g induced islet neogenesis is similar to embryonic islet morphogenesis and offers a model system for studying factors modulating islet development. Additionally, the duct cells occasionally transdifferentiate to gastrointestinal-like cell types and hepatocytes. These results underscore the lymphokine's ability to initiate a complex ‘transdifferentiation’ pathway, providing a window for understanding lineage interrelationships within a terminally differentiated structure.

scholarly journals The retinoblastoma protein-binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice.

1994 ◽  
Vol 14 (10) ◽  
pp. 6743-6754 ◽  
Author(s):  
L Fromm ◽  
W Shawlot ◽  
K Gunning ◽  
J S Butel ◽  
P A Overbeek
Keyword(s):  
Cell Cycle ◽  
Transgenic Mice ◽  
Retinoblastoma Protein ◽  
Simian Virus 40 ◽  
Cell Types ◽  
Simian Virus ◽  
T Antigen ◽  
Lens Fiber ◽  
Large T Antigen ◽  
Fiber Cells

Regulation of the cell cycle is a critical aspect of cellular proliferation, differentiation, and transformation. In many cell types, the differentiation process is accompanied by a loss of proliferative capability, so that terminally differentiated cells become postmitotic and no longer progress through the cell cycle. In the experiments described here, the ocular lens has been used as a system to examine the role of the retinoblastoma protein (pRb) family in regulation of the cell cycle during differentiation. The ocular lens is an ideal system for such studies, since it is composed of just two cell types: epithelial cells, which are capable of proliferation, and fiber cells, which are postmitotic. In order to inactivate pRb in viable mice, genes encoding either a truncated version of simian virus 40 large T antigen or the E7 protein of human papillomavirus were expressed in a lens-specific fashion in transgenic mice. Lens fiber cells in the transgenic mice were found to incorporate bromodeoxyuridine, implying inappropriate entry into the cell cycle. Surprisingly, the lens fiber cells did not proliferate as tumor cells but instead underwent programmed cell death, resulting in lens ablation and microphthalmia. Analogous lens alterations did not occur in mice expressing a modified version of the truncated T antigen that was mutated in the binding domain for the pRb family. These experimental results indicate that the retinoblastoma protein family plays a crucial role in blocking cell cycle progression and maintaining terminal differentiation in lens fiber cells. Apoptotic cell death ensues when fiber cells are induced to remain in or reenter the cell cycle.

Lectins are sensitive tools for defining the differentiation programs of mouse gut epithelial cell lineages

1994 ◽  
Vol 266 (6) ◽  
pp. G987-G1003 ◽  
Author(s):  
P. Falk ◽  
K. A. Roth ◽  
J. I. Gordon
Keyword(s):  
Epithelial Cell ◽  
Transgenic Mice ◽  
Intestinal Epithelial Cell ◽  
Cell Lineage ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Intestinal Epithelial ◽  
Cell Lineages ◽  
Carbohydrate Specificities

We have used histochemical methods to survey the cellular patterns of binding of a panel of 45 lectins with well-defined carbohydrate specificities to sections prepared from various regions of the gastric-to-colonic axis of fetal, neonatal, and adult FVB/N mouse gut. The results suggest that lectins can be used as remarkably sensitive tools to describe the differentiation programs of gastric and intestinal epithelial cell lineages as a function of their position along the cephalocaudal axis of the gut and as a function of developmental stage. Studies of intestinal isografts and transgenic mice that express Simian virus-40 T antigen in enterocytes suggest that many of these cell lineage-specific and spatial patterns of glycoconjugate production can be established and maintained in the absence of exposure to luminal contents and in the presence of specific proliferative abnormalities. This lectin panel should be useful for operationally defining subpopulations of the principal gut epithelial cell lineages in normal strains of mice, for describing variations in gut epithelial cell differentiation programs in mutant and transgenic mice, and for recovering specific epithelial cell lineages or subpopulations.

Simultaneous Assessment of Prohormone Transport and Processing in Four Separate Islet Cell Types

Pancreas ◽  
1988 ◽  
Vol 3 (6) ◽  
pp. 700-713 ◽  
Author(s):  
Bryan D. Noe ◽  
Mylene Amherdt ◽  
Alain Perrelet ◽  
Lelio Orci
Keyword(s):  
Islet Cell ◽  
Cell Types ◽  
Islet Cell Types ◽  
Simultaneous Assessment

Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine

Development ◽  
1999 ◽  
Vol 126 (18) ◽  
pp. 4149-4156 ◽  
Author(s):  
G. Rindi ◽  
C. Ratineau ◽  
A. Ronco ◽  
M.E. Candusso ◽  
M. Tsai ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transgenic Mice ◽  
Peptide Yy ◽  
Cell Types ◽  
Enteroendocrine Cells ◽  
Cell Type ◽  
Normal Numbers ◽  
Enteroendocrine Cell ◽  
Developmental Relationship ◽  
Ganciclovir Treatment

The four cell types of gut epithelium, enteroendocrine cells, enterocytes, Paneth cells and goblet cells, arise from a common totipotent stem cell located in the mid portion of the intestinal gland. The secretin-producing (S) cell is one of at least ten cell types belonging to the diffuse neuroendocrine system of the gut. We have examined the developmental relationship between secretin cells and other enteroendocrine cell types by conditional ablation of secretin cells in transgenic mice expressing herpes simplex virus 1 thymidine kinase (HSVTK). Ganciclovir-treated mice showed markedly increased numbers of apoptotic cells at the crypt-villus junction. Unexpectedly, ganciclovir treatment induced nearly complete ablation of enteroendocrine cells expressing cholecystokinin and peptide YY/glucagon (L cells) as well as secretin cells, suggesting a close developmental relationship between these three cell types. In addition, ganciclovir reduced the number of enteroendocrine cells producing gastric inhibitory polypeptide, substance-P, somatostatin and serotonin. During recovery from ganciclovir treatment, the enteroendocrine cells repopulated the intestine in normal numbers, suggesting that a common early endocrine progenitor was spared. Expression of BETA2, a basic helix-loop-helix protein essential for differentiation of secretin and cholecystokinin cells was examined in the proximal small intestine. BETA2 expression was seen in all enteroendocrine cells and not seen in nonendocrine cells. These results suggest that most small intestinal endocrine cells are developmentally related and that a close developmental relationship exists between secretin-producing S cells and cholecystokinin-producing and L type enteroendocrine cells. In addition, our work shows the existence of a multipotent endocrine-committed cell type and locates this hybrid multipotent cell type to a region of the intestine populated by relatively immature cells.

An experimental investigation into the possible origin of pancreatic islet cells from rhombencephalic neurectoderm

Development ◽  
1979 ◽  
Vol 52 (1) ◽  
pp. 23-38
Author(s):  
Ann Andrew ◽  
Beverley Kramer
Keyword(s):  
Pancreatic Islet ◽  
Islet Cell ◽  
Islet Cells ◽  
Cell Types ◽  
Nuclear Marker ◽  
Electron Microscopic ◽  
Pancreatic Islet Cell ◽  
Enteric Ganglia ◽  
Microscopic Features ◽  
Islet Cell Types

To determine whether or not any pancreatic islet cell type arises from rhombencephalic levels of neurectoderm, lengths of presumptive rhombencephalon (containing potential neural crest) of Black Australorp chick embryos at 6- to 9-somite stages were replaced isotopically and isochronically by neural tube of Japanese quail embryos. Some transplants included mesencephalic regions. In some cases various levels of the rhombencephalon were deleted and not replaced. The quail nuclear marker was detected in cranial ganglia in operated embryos sacrificed at 3¾ days of incubation and in enteric ganglia and cells accompanying some pancreatic nerves, in embryos killed at 7 days of incubation. This provided evidence of normal migration of crest cells from the grafts. Dopa was administered to the younger embryos, which were submitted to the formaldehyde-induced fluorescence procedure to demonstrate APUD (Amine Precursor Uptake and Decarboxylation) cells. No pancreatic APUD cells exhibited the quail nuclear marker. In 9- to 11-day embryos, A and B cells were identified by specific light and electron microscopic features. None showed the quail marker. The marker was also absent from those D cells seen and from cells of an as yet unidentified type, but not enough of these were found to warrant a conclusion. All islet cell types were found in embryos from which various levels of the rhombencephalon had been deleted. It is concluded that at least A and B islet cells are not derived from the rhombencephalic neurectoderm and probably not from mesencephalic levels. Their most likely origin remains the endoderm, which was the accepted source until recently

Use of transgenic mice reveals cell-specific transformation by a simian virus 40 T-antigen amino-terminal mutant

1993 ◽  
Vol 13 (6) ◽  
pp. 3255-3265
Author(s):  
H S Symonds ◽  
S A McCarthy ◽  
J Chen ◽  
J M Pipas ◽  
T Van Dyke
Keyword(s):  
Cell Growth ◽  
T Lymphocytes ◽  
Transgenic Mice ◽  
Choroid Plexus ◽  
Simian Virus 40 ◽  
Cell Types ◽  
Simian Virus ◽  
T Antigen ◽  
Cellular Proteins ◽  
Amino Terminal

We have used the multifunctional transforming protein, simian virus 40 T antigen, as a probe to study the mechanisms of cell growth regulation in the intact organism. T antigen appears to perturb cell growth, at least in part, by stably interacting with specific cellular proteins that function to maintain normal cell growth properties. Experiments in cultured cells indicate that at least three distinct regions of simian virus 40 T antigen have roles in transformation. Two regions correlate with the binding of known cellular proteins, p53, pRB, and p107. A third activity, located near the amino terminus, has been defined genetically but not biochemically. By targeting expression of wild-type and mutant forms of T antigen to distinct cell types in transgenic mice, we have begun to systematically determine which activities play a role in tumorigenesis of each cell type. In this study, we sought to determine the role of the amino-terminal transformation function with such an analysis of the T-antigen mutant dl1135. This protein, which lacks amino acids 17 to 27, retains the p53-, pRB-, and p107-binding activities yet fails to transform cells in culture. To direct expression in transgenic mice, we used the lymphotropic papovavirus transcriptional signals that are specific for B and T lymphocytes and the choroid plexus epithelium of the brain. We show here that although defective in cell culture, dl1135 specifically induced the development of thymic lymphomas in the mouse. Expression of the protein was routinely observed in B- and T-lymphoid cells, although B-cell abnormalities were not observed. Choroid plexus tumors were observed only infrequently; however, dl1135 was not consistently expressed in this tissue. Within a given transgenic line, the penetrance of T-cell tumorigenesis was 100% but appeared to require secondary events, as judged from the clonal nature of the tumors. These experiments suggest that the amino-terminal region of T antigen has a role in the transformation of certain cell types (such as fibroblasts in culture and B lymphocytes) but is dispensable for the transformation of T lymphocytes.

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