Genomes and Genes
Gene Symbol: Ins1
Description: insulin I
Alias: Ins-1, Ins2-rs1, insulin-1
- Wang S, Yan J, Anderson D, Xu Y, Kanal M, Cao Z, et al. Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas. Dev Biol. 2010;339:26-37 pubmed publisher..The control of Neurog3+ cell number and the Neurog3 threshold-dependent endocrine differentiation mechanism combine to select a specific proportion of pancreatic progenitor cells to adopt the islet cell fate. ..
- Mellitzer G, Beucher A, Lobstein V, Michel P, Robine S, Kedinger M, et al. Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival. J Clin Invest. 2010;120:1708-21 pubmed publisher..Our data help unravel the role of enteroendocrine cells and hormones in lipid absorption and maintenance of the intestinal epithelium. ..
- Wang S, Zhang J, Zhao A, Hipkens S, Magnuson M, Gu G. Loss of Myt1 function partially compromises endocrine islet cell differentiation and pancreatic physiological function in the mouse. Mech Dev. 2007;124:898-910 pubmed..The consequences of Myt1 inactivation in the developing pancreas could be masked by activation of its paralogs, Myt1l and Myt3. These findings suggest Myt1 is involved in proper endocrine differentiation and function. ..
- Mellitzer G, Bonne S, Luco R, Van De Casteele M, Lenne Samuel N, Collombat P, et al. IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas. EMBO J. 2006;25:1344-52 pubmed..IA1 is therefore a novel Ngn3-regulated factor required for normal differentiation of pancreatic endocrine cells. ..
- Lamotte L, Jackerott M, Bucchini D, Jami J, Joshi R, Deltour L. Knock-in of diphteria toxin A chain gene at Ins2 locus: effects on islet development and localization of Ins2 expression in the brain. Transgenic Res. 2004;13:463-73 pubmed..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. ..
- Krapp A, Knöfler M, Frutiger S, Hughes G, Hagenbuchle O, Wellauer P. The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein. EMBO J. 1996;15:4317-29 pubmed..Thus the pancreas-specific DNA-binding activity of PTF1 originates from the synthesis of at least one cell-specific component rather than from a cell-specific assembly of more widely distributed proteins. ..
- Kordowich S, Collombat P, Mansouri A, Serup P. Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage. BMC Dev Biol. 2011;11:52 pubmed publisher..Our analysis also suggests that one of the coupled functions of Nkx2.2 and Pax4 is to counteract Arx gene activity in early committed beta-cells. ..
- Carbe C, Hertzler Schaefer K, Zhang X. The functional role of the Meis/Prep-binding elements in Pax6 locus during pancreas and eye development. Dev Biol. 2012;363:320-9 pubmed publisher..Together, these results provide functional evidence for the independent and synergistic roles of the Pax6 upstream enhancers, and they suggest the potential redundancy of Meis/Prep protein in Pax6 regulation...
- Kido Y, Nakae J, Hribal M, Xuan S, Efstratiadis A, Accili D. Effects of mutations in the insulin-like growth factor signaling system on embryonic pancreas development and beta-cell compensation to insulin resistance. J Biol Chem. 2002;277:36740-7 pubmed..We conclude that Igf1r and Insr are required for embryonic development of the exocrine but not of the endocrine pancreas and that defects of Igf1r do not alter glucose homeostasis as long as the insulin receptor system remains intact. ..
- Schwitzgebel V, Scheel D, Conners J, Kalamaras J, Lee J, Anderson D, et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development. 2000;127:3533-42 pubmed
- Pedersen I, Klinck R, Hecksher Sorensen J, Zahn S, Madsen O, Serup P, et al. Generation and characterization of monoclonal antibodies against the transcription factor Nkx6.1. J Histochem Cytochem. 2006;54:567-74 pubmed..The presented antibodies are useful tools for the further characterization of the role and function of Nkx6.1 in pancreatic development, especially for use in double-labeling experiments with existing polyclonal rabbit antibodies. ..
- Cano D, Murcia N, Pazour G, Hebrok M. Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Development. 2004;131:3457-67 pubmed..Thus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas. ..
- Henseleit K, Nelson S, Kuhlbrodt K, Hennings J, Ericson J, Sander M. NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas. Development. 2005;132:3139-49 pubmed..We demonstrate that expression of Myt1 depends on overall Nkx6 gene dose, and therefore identify Myt1 as a possible downstream target of Nkx6 genes in the endocrine differentiation pathway. ..
- Artner I, Hang Y, Mazur M, Yamamoto T, Guo M, Lindner J, et al. MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes. 2010;59:2530-9 pubmed publisher..Our results provide insight into the sequential manner by which MafA and MafB regulate islet ?-cell formation and maturation. ..
- Dubois C, Shih H, Seymour P, Patel N, Behrmann J, Ngo V, et al. Sox9-haploinsufficiency causes glucose intolerance in mice. PLoS ONE. 2011;6:e23131 pubmed publisher..Our findings show Sox9 plays an important role in endocrine development by maintaining Ngn3 and Pdx1 expression. Glucose intolerance in Sox9-haploinsufficient mice suggests that mutations in Sox9 could play a role in diabetes in humans. ..
- Jensen J, Heller R, Funder Nielsen T, Pedersen E, Lindsell C, Weinmaster G, et al. Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes. 2000;49:163-76 pubmed..Dynamic expression of Notch1 in PDX+ epithelial cells suggests that Notch signaling could inhibit a Ngn-NeuroD cascade as seen in the nervous system and thus prevent premature differentiation of endocrine cells. ..
- Furuta M, Carroll R, Martin S, Swift H, Ravazzola M, Orci L, et al. Incomplete processing of proinsulin to insulin accompanied by elevation of Des-31,32 proinsulin intermediates in islets of mice lacking active PC2. J Biol Chem. 1998;273:3431-7 pubmed
- Collombat P, Hecksher Sørensen J, Broccoli V, Krull J, Ponte I, Mundiger T, et al. The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development. 2005;132:2969-80 pubmed..Finally, our data provide evidence that both Arx and Pax4 act as transcriptional repressors that control the expression level of one another, thereby mediating proper endocrine fate allocation. ..
- Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005;435:220-3 pubmed..We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain ..
- Liu J, Hunter C, Du A, Ediger B, Walp E, Murray J, et al. Islet-1 regulates Arx transcription during pancreatic islet alpha-cell development. J Biol Chem. 2011;286:15352-60 pubmed publisher..Isl-1 represents the first known activator of Arx transcription in ?-cells, here established to be acting through the conserved Re1 and Re2 control domains. ..
- Duvillie B, Bucchini D, Tang T, Jami J, Paldi A. Imprinting at the mouse Ins2 locus: evidence for cis- and trans-allelic interactions. Genomics. 1998;47:52-7 pubmed..In addition, our data suggest that the two parental alleles may "communicate" with each other and influence the transcription at the locus. ..
- Chu K, Tsai M. Neuronatin, a downstream target of BETA2/NeuroD1 in the pancreas, is involved in glucose-mediated insulin secretion. Diabetes. 2005;54:1064-73 pubmed..These results suggest for the first time an important role for NNAT in insulin secretion and for proper beta-cell function. ..
- Deltour L, VanDamme J, Jouvenot Y, Duvillie B, Kelemen K, Schaerly P, et al. Differential expression and imprinting status of Ins1 and Ins2 genes in extraembryonic tissues of laboratory mice. Gene Expr Patterns. 2004;5:297-300 pubmed..In the present study we have re-examined the imprinting status of Ins1. We found that Ins1 is not expressed in the yolk sac of several laboratory mouse strains...
- Collombat P, Mansouri A, Hecksher Sorensen J, Serup P, Krull J, Gradwohl G, et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 2003;17:2591-603 pubmed..We propose that the antagonistic functions of Arx and Pax4 for proper islet cell specification are related to the pancreatic levels of the respective transcripts. ..
- Bhushan A, Itoh N, Kato S, Thiery J, Czernichow P, Bellusci S, et al. Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development. 2001;128:5109-17 pubmed..These results indicate that Fgf10 signalling is required for the normal development of the pancreas and should prove useful in devising methods to expand pancreatic progenitor cells. ..
- Desgraz R, Herrera P. Pancreatic neurogenin 3-expressing cells are unipotent islet precursors. Development. 2009;136:3567-74 pubmed publisher..We propose a model whereby Ngn3(+) cells are monotypic (i.e. unipotent) precursors, and use this paradigm to refocus ideas on how cell number and type must be regulated in building complete islets of Langerhans. ..
- Doyle M, Loomis Z, Sussel L. Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet. Development. 2007;134:515-23 pubmed..2 through its TN domain. These studies suggest that Nkx2.2 functions predominantly as a transcriptional repressor during specification of endocrine cell types in the pancreas. ..
- Seymour P, Freude K, Dubois C, Shih H, Patel N, Sander M. A dosage-dependent requirement for Sox9 in pancreatic endocrine cell formation. Dev Biol. 2008;323:19-30 pubmed publisher..Our findings therefore suggest that defective endocrine specification might underlie the pancreatic phenotype of individuals with CD. ..
- Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, et al. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development. 2000;127:5533-40 pubmed..Together, these experiments reveal two independently controlled pathways for beta-cell differentiation, and place Nkx6.1 downstream of Nkx2.2 in the major pathway of beta-cell differentiation. ..
- Norgaard G, Jensen J, Jensen J. FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development. Dev Biol. 2003;264:323-38 pubmed..These data suggest that FGF10 signaling serves to integrate cell growth and terminal differentiation at the level of Notch activation, revealing a novel second role of this key signaling system during pancreatic development. ..
- Fujikura J, Hosoda K, Iwakura H, Tomita T, Noguchi M, Masuzaki H, et al. Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas. Cell Metab. 2006;3:59-65 pubmed..Thus, our analyses indicate that Notch/Rbp-j signaling prevents premature differentiation of pancreatic progenitor cells into endocrine and ductal cells during early development of the pancreas. ..
- Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner Weir S, et al. A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol. 2006;293:526-39 pubmed..Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth. ..
- Anderson K, Torres C, Solomon K, Becker T, Newgard C, Wright C, et al. Cooperative transcriptional regulation of the essential pancreatic islet gene NeuroD1 (beta2) by Nkx2.2 and neurogenin 3. J Biol Chem. 2009;284:31236-48 pubmed publisher..Collectively, these findings further define the conserved regulatory networks involved in islet beta cell formation and function. ..
- Suzuki A, Nakauchi H, Taniguchi H. Glucagon-like peptide 1 (1-37) converts intestinal epithelial cells into insulin-producing cells. Proc Natl Acad Sci U S A. 2003;100:5034-9 pubmed..Our findings suggest that efficient induction of insulin production in intestinal epithelial cells by GLP-1-(1-37) could represent a new therapeutic approach to diabetes mellitus. ..
- Vuguin P, Kedees M, Cui L, Guz Y, Gelling R, Nejathaim M, et al. Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology. 2006;147:3995-4006 pubmed..These findings suggest that GLU participates in a feedback loop that regulates the proportion of the different endocrine cell types in islets, the number of islets per pancreas, and development of the mature alpha-cell phenotype. ..
- Gannon M, Ray M, Van Zee K, Rausa F, Costa R, Wright C. Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function. Development. 2000;127:2883-95 pubmed
- Schaffer A, Taylor B, Benthuysen J, Liu J, Thorel F, Yuan W, et al. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet. 2013;9:e1003274 pubmed publisher..Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC)-derived insulin(+) cells, our study has significant implications for developing cell replacement therapies. ..
- Kuroda A, Rauch T, Todorov I, Ku H, Al Abdullah I, Kandeel F, et al. Insulin gene expression is regulated by DNA methylation. PLoS ONE. 2009;4:e6953 pubmed publisher..Our findings suggest that insulin promoter CpG demethylation may play a crucial role in beta cell maturation and tissue-specific insulin gene expression. ..
- Zhang H, Ackermann A, Gusarova G, Lowe D, Feng X, Kopsombut U, et al. The FoxM1 transcription factor is required to maintain pancreatic beta-cell mass. Mol Endocrinol. 2006;20:1853-66 pubmed..These results suggest that mechanisms regulating embryonic beta-cell proliferation differ from those used postnatally to maintain the differentiated cell population. ..
- Fujitani Y, Fujitani S, Boyer D, Gannon M, Kawaguchi Y, Ray M, et al. Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation. Genes Dev. 2006;20:253-66 pubmed
- Levisetti M, Suri A, Petzold S, Unanue E. The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form. J Immunol. 2007;178:6051-7 pubmed..The insulin peptides represent another example of a weak MHC-binding ligand that is highly immunogenic, giving rise to distinct populations of autoimmune T cells. ..
- Mellitzer G, Martin M, Sidhoum Jenny M, Orvain C, Barths J, Seymour P, et al. Pancreatic islet progenitor cells in neurogenin 3-yellow fluorescent protein knock-add-on mice. Mol Endocrinol. 2004;18:2765-76 pubmed..The Ngn3(EYFP) mice represent a valuable tool to study islet cell development and neogenesis in normal and diabetic animals as well as for the determination of the conditions to generate beta-cells in vitro. ..
- Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener D. PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab. 2006;4:491-7 pubmed
- Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest. 2004;114:963-8 pubmed
- Perez S, Cano D, Dao Pick T, Rougier J, Werb Z, Hebrok M. Matrix metalloproteinases 2 and 9 are dispensable for pancreatic islet formation and function in vivo. Diabetes. 2005;54:694-701 pubmed..However, islet formation is unaffected in transgenic mice with modified tissue inhibitor of metalloproteinase-1 (TIMP1) levels, suggesting that MMP activity may contribute little to islet morphogenesis in vivo. ..
- Schaffer A, Freude K, Nelson S, Sander M. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell. 2010;18:1022-9 pubmed publisher..Thus, cross-antagonism between Nkx6 and Ptf1a in multipotent progenitors governs the equilibrium between endocrine and acinar cell neogenesis required for normal pancreas development. ..
- Harrison K, Thaler J, Pfaff S, Gu H, Kehrl J. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet. 1999;23:71-5 pubmed..Hlxb9-/- beta-cells express low levels of the glucose transporter Glut2 and homeodomain factor Nkx 6-1. Thus, Hlxb9 is key to normal pancreas development and function. ..
- Leroux L, Desbois P, Lamotte L, Duvillie B, Cordonnier N, Jackerott M, et al. Compensatory responses in mice carrying a null mutation for Ins1 or Ins2. Diabetes. 2001;50 Suppl 1:S150-3 pubmed..retardation and postnatal acute diabetes result from insulin deficiency in double homozygous null mutants for Ins1 and Ins2 (Duvillié B, et al., Proc. Natl. Acad. Sci. USA 94:5137-5140, 1997)...
- Jiang Y, Nishimura W, Devor Henneman D, Kusewitt D, Wang H, Holloway M, et al. Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin. Diabetes. 2008;57:2718-27 pubmed publisher..Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in beta-cell regulation in diseased states, such as diabetes. ..
- Huotari M, Miettinen P, Palgi J, Koivisto T, Ustinov J, Harari D, et al. ErbB signaling regulates lineage determination of developing pancreatic islet cells in embryonic organ culture. Endocrinology. 2002;143:4437-46 pubmed..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. ..
- Brissova M, Shostak A, Shiota M, Wiebe P, Poffenberger G, Kantz J, et al. Pancreatic islet production of vascular endothelial growth factor--a is essential for islet vascularization, revascularization, and function. Diabetes. 2006;55:2974-85 pubmed..Factors modulating VEGF-A expression may influence islet vascularity and, consequently, the amount of insulin delivered into the systemic circulation. ..
- Heiser P, Lau J, Taketo M, Herrera P, Hebrok M. Stabilization of beta-catenin impacts pancreas growth. Development. 2006;133:2023-32 pubmed..Taken together, these data suggest a previously unappreciated temporal/spatial role for beta-catenin signaling in the regulation of pancreas organ growth. ..
- Lee C, Sund N, Behr R, Herrera P, Kaestner K. Foxa2 is required for the differentiation of pancreatic alpha-cells. Dev Biol. 2005;278:484-95 pubmed..By marker gene analysis, we show that the expression of the alpha-cell transcription factors Arx, Pax6, and Brn4 does not require Foxa2 in the transcriptional hierarchy governing alpha-cell differentiation. ..
- Hart A, Papadopoulou S, Edlund H. Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells. Dev Dyn. 2003;228:185-93 pubmed..Together, our data suggest a role for FGF10/FGFR2b signalling in regulation of pancreatic cell proliferation and differentiation and that FGF10/FGFR2b signalling affects the Notch-mediated lateral inhibition pathway. ..
- Krapp A, Knöfler M, Ledermann B, Burki K, Berney C, Zoerkler N, et al. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 1998;12:3752-63 pubmed
- Esni F, Taljedal I, Perl A, Cremer H, Christofori G, Semb H. Neural cell adhesion molecule (N-CAM) is required for cell type segregation and normal ultrastructure in pancreatic islets. J Cell Biol. 1999;144:325-37 pubmed..Possible mechanisms underlying this phenomenon may include changes in cadherin-mediated adhesion and cell polarity. ..
- Seymour P, Freude K, Tran M, Mayes E, Jensen J, Kist R, et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci U S A. 2007;104:1865-70 pubmed..These findings will be of major significance for the development of in vitro protocols for cell replacement therapies. ..
- Greiner T, Kesavan G, Ståhlberg A, Semb H. Rac1 regulates pancreatic islet morphogenesis. BMC Dev Biol. 2009;9:2 pubmed publisher..Our results further emphasize Rac1 as a key regulator of cell migration and cell adhesion during tissue and organ morphogenesis. ..
- Stiles B, Kuralwalla Martinez C, Guo W, Gregorian C, Wang Y, Tian J, et al. Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes. Mol Cell Biol. 2006;26:2772-81 pubmed..Our data demonstrate that PTEN loss in beta cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for beta-cell protection and regeneration therapies. ..
- Johansson J, Voss U, Kesavan G, Kostetskii I, Wierup N, Radice G, et al. N-cadherin is dispensable for pancreas development but required for beta-cell granule turnover. Genesis. 2010;48:374-81 pubmed publisher..The number of insulin secretory granules is significantly reduced in N-cadherin-deficient beta-cells, and as a consequence insulin secretion is decreased. ..
- Li S, Francisco A, Munroe R, Schimenti J, Long Q. SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells. BMC Dev Biol. 2010;10:19 pubmed publisher..Together, these data suggest that Sel1l is essential for the growth and differentiation of endoderm-derived pancreatic epithelial cells during mouse embryonic development. ..
- Ma F, Haumaitre C, Chen F, Han Z. Comparison of murine embryonic pancreatic development in vitro and in vivo. Pancreas. 2011;40:1012-7 pubmed publisher..The development of the murine pancreas cultured at the air-medium interface mimicked that of pancreas in vivo. Our simple culture system might offer the potential of a source of mature ? cells. ..
- Diaferia G, Jimenez Caliani A, Ranjitkar P, Yang W, Hardiman G, Rhodes C, et al. ?1 integrin is a crucial regulator of pancreatic ?-cell expansion. Development. 2013;140:3360-72 pubmed publisher..Collectively, our results demonstrate that ?1 integrin receptors function as crucial positive regulators of ?-cell expansion. ..
- Sosa Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 1997;386:399-402 pubmed..A default pathway would explain the elevated number of alpha cells in the absence of Pax4. ..
- Gannon M, Ables E, Crawford L, Lowe D, OFFIELD M, Magnuson M, et al. pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis. Dev Biol. 2008;314:406-17 pubmed
- CHAO C, Loomis Z, Lee J, Sussel L. Genetic identification of a novel NeuroD1 function in the early differentiation of islet alpha, PP and epsilon cells. Dev Biol. 2007;312:523-32 pubmed..Furthermore, this study reveals a previously unappreciated early function of NeuroD1 in regulating the specification of alpha, PP and epsilon cells. ..
- Artner I, Blanchi B, Raum J, Guo M, Kaneko T, Cordes S, et al. MafB is required for islet beta cell maturation. Proc Natl Acad Sci U S A. 2007;104:3853-8 pubmed..These results demonstrate that MafB plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature alpha and beta cells. ..
- Gao N, LeLay J, Vatamaniuk M, Rieck S, Friedman J, Kaestner K. Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev. 2008;22:3435-48 pubmed publisher..Thus, the regulation of Pdx1 expression by Foxa1 and Foxa2 is a key early event controlling the expansion and differentiation of the pancreatic primordia. ..
- Nekrep N, Wang J, Miyatsuka T, German M. Signals from the neural crest regulate beta-cell mass in the pancreas. Development. 2008;135:2151-60 pubmed publisher..2 form a non-cell-autonomous feedback loop that links the neural crest with the pancreatic epithelium, regulates the size of the beta-cell population, and thereby impacts insulin-secretory capacity and energy homeostasis. ..
- Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43:34-41 pubmed publisher..These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status. ..
- Meur G, Qian Q, Da Silva Xavier G, Pullen T, Tsuboi T, McKinnon C, et al. Nucleo-cytosolic shuttling of FoxO1 directly regulates mouse Ins2 but not Ins1 gene expression in pancreatic beta cells (MIN6). J Biol Chem. 2011;286:13647-56 pubmed publisher..and insulin-stimulated nuclear shuttling of FoxO1 in pancreatic ? cells and its consequences for preproinsulin (Ins1, Ins2) gene expression...
- Sander M, Neubüser A, Kalamaras J, Ee H, Martin G, German M. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 1997;11:1662-73 pubmed..Biochemical studies identify wild-type PAX6 protein as the transcription factor that binds to a common element in the glucagon, insulin, and somatostatin promoters, and show that PAX6 transactivates the glucagon and insulin promoters. ..
- Kone M, Pullen T, Sun G, Ibberson M, Martinez Sanchez A, Sayers S, et al. LKB1 and AMPK differentially regulate pancreatic Î²-cell identity. FASEB J. 2014;28:4972-85 pubmed publisher..Highly Î²-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis...
- Mehran A, Templeman N, Brigidi G, Lim G, Chu K, Hu X, et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 2012;16:723-37 pubmed publisher..We examined the role of insulin hypersecretion in diet-induced obesity by varying the pancreas-specific Ins1 gene dosage in mice lacking Ins2 gene expression in the pancreas, thymus, and brain...
- Papadopoulou S, Edlund H. Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes. 2005;54:2844-51 pubmed..Collectively, our data provide evidence that Wnt signaling is required for pancreatic growth but not adult beta-cell function. ..
- Artner I, Le Lay J, Hang Y, Elghazi L, Schisler J, Henderson E, et al. MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells. Diabetes. 2006;55:297-304 pubmed..These results indicate that MafB is not only important to islet alpha-cell function but may also be involved in regulating genes required in both endocrine alpha- and beta-cell differentiation. ..
- Miyatsuka T, Kosaka Y, Kim H, German M. Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a. Proc Natl Acad Sci U S A. 2011;108:185-90 pubmed publisher..These studies reveal a crucial role for Neurog3 in regulating the cell cycle during the differentiation of islet cells and demonstrate that the subsequent down-regulation of Neurog3 allows the mature islet cell population to expand. ..
- Hald J, Hjorth J, German M, Madsen O, Serup P, Jensen J. Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Dev Biol. 2003;260:426-37 pubmed
- Duvillie B, Currie C, Chrones T, Bucchini D, Jami J, Joshi R, et al. Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to beta-cell hyperplasia in mutant mice lacking insulin. Endocrinology. 2002;143:1530-7 pubmed..A significant increase in the mean area of the islets was found at embryonic d 18.5 (E18.5) and in the newborn in Ins1-/-, Ins2-/- animals compared with Ins1-/-, Ins2+/- and wild-type controls, whereas the blood glucose levels were ..
- Smart N, Apelqvist A, Gu X, Harmon E, Topper J, Macdonald R, et al. Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus. PLoS Biol. 2006;4:e39 pubmed..Thus, our studies reveal that TGF-beta signaling is crucial for establishing and maintaining defining features of mature pancreatic beta cells. ..
- Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science. 2001;294:564-7 pubmed..These results indicate that vessels not only provide metabolic sustenance, but also provide inductive signals for organ development. ..