Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that cells transiently expressing tyrosine hydroxylase (TH), the first enzyme of the catecholamine biosynthetic pathway, are present in the pancreas of mouse embryos from prenatal Day 11 (E11) and that, at E12, some TH cells contain glucagon. Cells containing TH were also found in adults which, unlike the TH cells of embryos, did not contain glucagon (G. Teitelman, T. H. Joh, and D. J. Reis (1981). Proc. Natl. Acad. Sci. 78, 5225). These findings suggested to us that the TH cells of embryonic pancreas were the precursors of glucagon cells of adults. In this study we used immunocytochemical and autoradiographic techniques to determine whether cells containing TH (a) were present in pancreas throughout pre- and postnatal development, (b) were localized to a specific region of the gland, (c) contained insulin at any time, and (d) proliferated. We found that TH cells were present in pancreas throughout life. In embryos, cells containing TH localized only along the pancreatic duct, also contained either glucagon or insulin, and were able to proliferate. In contrast, after birth, the pancreatic duct contained no TH cells. Cells containing TH in postnatal and adult mice also differed from embryonic TH cells in that they were found in all islets, contained insulin but not glucagon, and did not synthesize DNA, and hence did not proliferate. These findings suggest that progenitor cells that contain catecholamines and are present in the pancreatic duct give rise to glucagon and insulin cells of adult islets. They also indicate that the TH-insulin cells of postnatal and adult mice are not stem cells but are postmitotic cells that appear in the islets after birth.
 ...
PMID:Cell lineage analysis of pancreatic islet development: glucagon and insulin cells arise from catecholaminergic precursors present in the pancreatic duct. 288 53

It has been suggested that members of the neuropeptide Y (NPY) family of regulatory peptides [NPY, peptide YY (PYY) and pancreatic polypeptide (PP)] play an important role in the development of the endocrine pancreas. The development of rat endocrine pancreas from embryonic (E) day 12 until 30 days postpartum (P) was studied with emphasis on NPY, PYY and PP and their co-existence with insulin, glucagon and somatostatin using single and double immunostaining and in situ hybridization. Already at E12, PYY was detectable in small endocrine cell clusters and found to be co-localised with both insulin and glucagon, which at this stage occurred in the same cells. At E16 most of the insulin-immunoreactive (IR) cells were distinct from the glucagon/PYY-IR cells. Interestingly, at E16 NPY mRNA, and at E17 NPY immunoreactivity appeared in a few, scattered endocrine cells. Virtually all NPY-IR endocrine cells were insulin-producing beta cells. At E18 the endocrine cells started to form typical islets with centrally located insulin/NPY-IR cells surrounded by glucagon/PYY-IR cells. AT E20-E21, the vast majority of insulin-producing cells also expressed NPY. However, at birth (day 0) islet cell NPY mRNA was lacking. Postnatally the number and immunostaining intensity of NPY-IR islet cells rapidly declined, being non-detectable at P5. Cells containing PP immunoreactivity and PP mRNA were first detected at E21. The adult pattern of islet peptide distribution, with NPY confined to neuronal elements. PYY and PP exclusively in endocrine cells, was established at P5. The beta cell expression of NPY during the latter part of embryogenesis coincides with the prepartal glucocorticoid surge and with rapid islet cell replication and differentiation. This is compatible with steroid induction of NPY expression and with a role for NPY in the maturation of beta cells and their hormone release, which occurs in the immediate neonatal period.
 ...
PMID:Developmental expression of NPY, PYY and PP in the rat pancreas and their coexistence with islet hormones. 910 Feb 83

In this study, we have investigated the role of the embryonic mesenchyme in the development of the pancreas. We have compared the development in vitro of E12.5 rat pancreatic rudiments grown in the presence or absence of mesenchyme. When the E12.5 pancreatic epithelial rudiment is cultured in the presence of its surrounding mesenchyme, both morphogenesis and cytodifferentiation of the exocrine component of the pancreas are completely achieved, while only a few immature endocrine cells develop. The pancreatic rudiments grown in the absence of mesenchyme develop in a completely different way; the exocrine tissue develops poorly and fails to undergo acinar morphogenesis, while the endocrine tissue develops actively. Four times more insulin-positive cells develop after removal of the mesenchyme than in the cultures performed in the presence of mesenchyme. Moreover, the insulin-expressing cells developed in the mesenchyme-depleted rudiments appear mature since they do not coexpress glucagon, express the glucose transporter Glut-2 and express Rab3A, a molecule associated with the secretory granules. Moreover, these endocrine cells are able to associate and form true islets. Both the inductive effect of the mesenchyme on the proper development of the exocrine tissue and its repressive effect on the development of the endocrine cells are mediated by soluble factors. Follistatin, which is expressed by E12.5 pancreatic mesenchyme, can mimic both inductive and repressive effects of the mesenchyme. Follistatin could thus represent one of the mesenchymal factors required for the development of the exocrine tissue while exerting a repressive role on the differentiation of the endocrine cells.
 ...
PMID:Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. 946 48

Activin, a member of the transforming growth factor-beta superfamily, has been shown to be a critical regulator in exocrine and endocrine pancreas formation. The purpose of our study was to describe the ontogeny of activin B and its inhibitor, follistatin, in developing pancreas and to elucidate potential mechanisms for exocrine and endocrine lineage selection. Mouse embryonic pancreata were dissected at various ages (day 10 [E10.5] to birth [E18.5]), sectioned, and immunostained for activin B (one of two existing isomers, A and B), follistatin, insulin, and glucagon. In addition, reverse transcriptase-polymerase chain reaction was employed to determine the messenger RNA expression of follistatin in isolated pancreatic epithelia and mesenchyme of various ages. Activin B was first detected at E12.5 in epithelial cells coexpressing glucagon. At E16.5 these coexpressors appeared as clusters in close proximity to early ducts. By E18.5 activin B was localized to forming islets where cells coexpressed glucagon and were arranged in the mantle formation characteristic of mature alpha cells. Follistatin was found to be ubiquitous in pancreatic mesenchyme at early ages by immunohistochemical analysis, disappearing sometime after E12.5. Follistatin reappeared in E18.5 islets and remains expressed in adult islets. Follistatin messenger RNA was first detected in epithelium at E11.5, preceding its protein expression in islets later in gestation. We propose that mesenchyme-derived follistatin inhibits epithelium-derived activin at early embryonic ages allowing for unopposed exocrine differentiation and relative suppression of endocrine differentiation. At later ages the decrease in the amount of mesenchyme relative to epithelium and the subsequent drop in follistatin levels liberates epithelial activin to allow differentiation of endocrine cells to form mature islets by the time of birth.
 ...
PMID:Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: implications for lineage selection. 1076 89

In rodents, the first insulin-producing cells appear in the pancreas at mid-gestation around embryonic day 11 (E11). However, on the basis of various features, such as morphology or hormonal coexpression, it is apparent that these initial insulin-expressing cells are different from those that develop after E15. In the present study, the pancreatic expression of both thyrotropin-releasing hormone (TRH) mRNA and insulin was studied during embryonic and fetal life. We report here that in the rat, while insulin mRNA is detected in the pancreas as early as E12, TRH mRNA cannot be detected before E16. At that stage and later on during fetal and early postnatal life, TRH mRNA is detected in insulin-producing cells, no signal being detected in other endocrine cell types or in exocrine tissue. It was also noted, by means of triple staining performed at E17, that the expression of TRH mRNA was restricted to insulin-expressing cells negative for glucagon, whereas the few insulin-expressing cells present at that stage, which coexpress insulin and glucagon, did not express TRH mRNA. Taken together, these data indicate that TRH is a marker of insulin-expressing cells, which develop after E15.
 ...
PMID:Pancreatic pattern of expression of thyrotropin-releasing hormone during rat embryonic development. 1097 42

The neuregulin (NRG)/epidermal growth factor (EGF) family of growth factors consists of several ligands that specifically activate four erbB receptor-tyrosine kinases, namely erbB-1 (EGF-R), erbB-2 (neu), erbB-3, and erbB-4. We have previously shown that islet morphogenesis is impaired and beta-cell differentiation delayed in mice lacking functional EGF-R [EGF-R (-/-)]. The present study aims to clarify which erbB ligands are important for islet development. Pancreatic expression of EGF, TGF-alpha, heparin-binding EGF, betacellulin (BTC), and NRG-4 was detected as early as embryonic d 13 (E13). Effects of these ligands were studied in E12.5 pancreatic explant cultures grown for 5 d ex vivo. None of the growth factors affected the ratio of endocrine to exocrine cells. However, significant effects within the endocrine cell populations were induced by EGF, BTC, and NRG-4. beta-Cell development was augmented by BTC, whereas the development of somatostatin-expressing delta-cells was stimulated by NRG-4. Both ligands decreased the numbers of glucagon-containing alpha-cells. The effect of BTC was abolished in the EGF-R (-/-) mice. A soluble erbB-4 binding fusion protein totally inhibited the effects of NRG-4 but not of BTC. Neutralization of endogenous NRG-4 activity in the model system effectively inhibited delta-cell development, indicating that this erbB4-ligand is an essential factor for delineation of the somatostatin-producing delta-cells. Our results suggest that ligands of the EGF-R/erbB-1 and erbB-4 receptors regulate the lineage determination of islet cells during pancreatic development. BTC, acting through EGF-R/erbB-1, is important for the differentiation of beta-cells. This could be applied in the targeted differentiation of stem cells into insulin-producing cells.
 ...
PMID:ErbB signaling regulates lineage determination of developing pancreatic islet cells in embryonic organ culture. 1239 41

We report here knock-in of diphteria toxin A chain (dta) gene at the Ins2 locus, using the strategy previously employed to insert lacZ under control of the Ins2 promoter. Mutant Ins2(dta/+), Ins2(dta/lacZ) or Ins2(lacZ/+) mouse pups were generated by breeding and analyzed to study the effects of toxigenetic beta-cell ablation on islet development and to localize the extrapancreatic Ins2 expression site in the brain. Ins2(dta/+) and Ins2(dta/lacZ) pups developed a severe diabetic ketoacidosis and died rapidly. Histological analysis of their pancreas revealed that beta-cells completely disappeared in their islets as evidenced by loss of lacZ activity or insulin immunonostaining. beta-cell ablation did not alter the size of other islet cell populations which were normal at birth, although the glucagon-cell population was reduced by 85% at embryonic day E12.5. In the brain, comparative analysis of lacZ expression in Ins2(lacZ/+) and Ins2(dta/laZ) mice identified the choroid plexus (CP) as a major Ins2 expression site. This finding was confirmed by RT-PCR analysis of insulin transcripts in RNAs prepared from microdissected wild-type CP. Transcripts for other key beta-cell markers, with the notable exception of Pdx-1, were also found in CP RNAs. These results must revive interest in studies focused on extrapancreatic insulin gene expression.
 ...
PMID:Knock-in of diphteria toxin A chain gene at Ins2 locus: effects on islet development and localization of Ins2 expression in the brain. 1558 70

In order to purify and characterize nestin-positive cells in the developing pancreas a transgenic mouse was generated, in which the enhanced green fluorescent protein (EGFP) was driven by the nestin second intronic enhancer and upstream promoter. In keeping with previous studies on the distribution of nestin, EGFP was expressed in the developing embryo in neurones in the brain, eye, spinal cord, tail bud and glial cells in the small intestine. In the pancreas there was no detectable EGFP at embryonic day 11.5 (E11.5). EGFP expression appeared at E12.5 and increased in intensity through E14.5, E18.5 and post-natal day 1. Flow cytometry was used to quantify and purify the EGFP positive population in the E15.5 pancreas. 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). They also expressed, at a lower level, PDX-1, Isl-1, and the islet hormones pancreatic polypeptide, glucagon and somatostatin as well as GLUT2, the stem cell marker ABCG2 and PECAM, a marker of endothelial cells. It was further shown by immunocytochemistry of the E15.5 pancreas that EGFP colocalised in separate subpopulations of cells that expressed nestin, insulin and amylase. These results support the conclusion that nestin expressing cells can give rise to both endocrine and exocrine cells. The ability to purify these putative progenitor cells may provide further insights into their properties and function.
 ...
PMID:Presence of endocrine and exocrine markers in EGFP-positive cells from the developing pancreas of a nestin/EGFP mouse. 1669 77

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene predispose patients to MEN1 that affects mainly endocrine tissues, suggesting important physiological functions of the gene in adult endocrine cells. Homozygous disruption of Men1 in mice causes embryonic lethality, whereas the eventual involvement of the gene in embryonic development of the endocrine cells remains unknown. Here, we show that homozygous Men1 knockout mice demonstrate a reduced number of glucagon-positive cells in the E12.5 pancreatic bud associated with apoptosis, whereas the exocrine pancreas development in these mice is not affected. Our data suggest that menin is involved in the survival of the early pancreatic endocrine cells during the first developmental transition. Furthermore, chimerism assay revealed that menin has an autonomous and specific effect on the development of islet cells. In addition, using pancreatic bud culture mimicking the differentiation of alpha- and beta-cells during the second transition, we show that loss of menin leads to the failure of endocrine cell development, altered pancreatic structure and a markedly decreased number of cells expressing neurogenin 3, indicating that menin is also required at this stage of the endocrine pancreas development. Taken together, our results suggest that menin plays an indispensable role in the development of the pancreatic endocrine cells.
 ...
PMID:Tumour suppressor menin is essential for development of the pancreatic endocrine cells. 1877 65

In humans, glucagon-like peptide (GLP-1) functions during adult life as an incretin hormone with anorexigenic and antidiabetogenic properties. Also, the therapeutic potential of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and in bolstering the maintenance of human mesenchymal stem cell (hMSC) stores by promoting the proliferation and cytoprotection of hMSC seems to be relevant. Since these observations suggest a role for GLP-1 during developmental processes, the aim of the present work was to characterize GLP-1 in early development as well as its gene targets in mouse embryonic stem (mES) cells. Mouse embryos E6, E8, and E10.5 and pluripotent mES were used for the inmunodetection of GLP-1 and GLP-1 receptor. Quantitative real-time PCR was used to determine the expression levels of GLP-1R in several tissues from E12.5 mouse embryos. Additionally, GLP-1 gene targets were studied in mES by multiple gene expression analyses. GLP-1 and its receptors were identified in mES and during embryonic development. In pluripotent mES, GLP-1 modified the expression of endodermal, ectodermal, and mesodermal gene markers as well as sonic hedgehog, noggin, members of the fibroblast and hepatic growth factor families, and others involved in pancreatic development. Additionally, GLP-1 promoted the expression of the antiapoptotic gene bcl2 and at the same time reduced proapoptotic caspase genes. Our results indicate that apart from the effects and therapeutic benefits of GLP-1 in adulthood, it may have additional gene targets in mES cells during embryonic life. Furthermore, the pathophysiological implications of GLP-1 imbalance in adulthood may have a counterpart during development.
 ...
PMID:New gene targets for glucagon-like peptide-1 during embryonic development and in undifferentiated pluripotent cells. 2171 36


1