Grg3/TLE3 and Grg1/TLE1 induce monohormonal pancreatic β-cells while repressing α-cell functions.
Grg3/TLE3 and Grg1/TLE1 induce monohormonal pancreatic β-cells while repressing α-cell functions.
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作者：
Metzger DE;Liu C;Ziaie AS;Naji A;Zaret KS
在胰腺中，α-和β-细胞具有一定程度的可塑性。多能细胞的体外分化主要产生α和多激素β样细胞，这表明在了解如何形成功能性单激素β细胞以及用于维持β细胞身份的内源性抑制机制方面存在空白。我们发现，从胚胎发育到成年，几乎所有β-细胞都表达共抑制因子Grg3。然而，Grg3在较少的新生α-细胞中表达，并随着内分泌细胞成熟进入成年期而逐渐从α-细胞中丢失。我们发现小鼠Grg3+/−β-细胞α特异性基因表达增加，并且Grg3+/−胰腺有更多的α-细胞和更多的多激素细胞，这表明Grg3是单激素β细胞身份的生理维持所必需的。Grg3在α-细胞中的异位表达抑制胰高血糖素和Arx， Pdx1的加入诱导Glut2的表达和葡萄糖反应性胰岛素的分泌。此外，我们发现Grg1是人类β细胞中主要表达的Groucho，但其功能与Grg3相似。总之，我们发现Grg3和Grg1建立了单激素β细胞的身份，Groucho家族成员可能是制造功能性β细胞的有用工具或标记。
In the pancreas, α- and β-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly α- and polyhormonal β-like cells, indicating a gap in understanding of how functional monohormonal β-cells are formed and of the endogenous repressive mechanisms used to maintain β-cell identity. We show that the corepressor Grg3 is expressed in almost all β-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent α-cells and is progressively lost from α-cells as endocrine cells mature into adulthood. We show that mouse Grg3+/− β-cells have increased α-specific gene expression, and Grg3+/− pancreata have more α-cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal β-cell identity. Ectopic expression of Grg3 in α-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human β-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal β-cell identity, and Groucho family members may be useful tools or markers for making functional β-cells.
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影响因子：
--
作者：
Gauthier, BR;Schwitzgebel, VM;Philippe, J
通讯作者：
Philippe, J
影响因子：
10.5
作者：
Collombat, P;Mansouri, A;Gruss, P
通讯作者：
Gruss, P
影响因子：
7.7
作者：
POITOUT, V;STOUT, LE;ROBERTSON, RP
通讯作者：
ROBERTSON, RP
影响因子：
30.8
作者：
Morris, Andrew P.;Voight, Benjamin F.;Teslovich, Tanya M.;Ferreira, Teresa;Segre, Ayellet V.;Steinthorsdottir, Valgerdur;Strawbridge, Rona J.;Khan, Hassan;Grallert, Harald;Mahajan, Anubha;Prokopenko, Inga;Kang, Hyun Min;Dina, Christian;Esko, Tonu;Fraser, Ross M.;Kanoni, Stavroula;Kumar, Ashish;Lagou, Vasiliki;Langenberg, Claudia;Luan, Jian'an;Lindgren, Cecilia M.;Mueller-Nurasyid, Martina;Pechlivanis, Sonali;Rayner, N. William;Scott, Laura J.;Wiltshire, Steven;Yengo, Loic;Kinnunen, Leena;Rossin, Elizabeth J.;Raychaudhuri, Soumya;Johnson, Andrew D.;Dimas, Antigone S.;Loos, Ruth J. F.;Vedantam, Sailaja;Chen, Han;Florez, Jose C.;Fox, Caroline;Liu, Ching-Ti;Rybin, Denis;Couper, David J.;Kao, Wen Hong L.;Li, Man;Cornelis, Marilyn C.;Kraft, Peter;Sun, Qi;van Dam, Rob M.;Stringham, Heather M.;Chines, Peter S.;Fischer, Krista;Fontanillas, Pierre;Holmen, Oddgeir L.;Hunt, Sarah E.;Jackson, Anne U.;Kong, Augustine;Lawrence, Robert;Meyer, Julia;Perry, John R. B.;Platou, Carl G. P.;Potter, Simon;Rehnberg, Emil;Robertson, Neil;Sivapalaratnam, Suthesh;Stancakova, Alena;Stirrups, Kathleen;Thorleifsson, Gudmar;Tikkanen, Emmi;Wood, Andrew R.;Almgren, Peter;Atalay, Mustafa;Benediktsson, Rafn;Bonnycastle, Lori L.;Burtt, Noel;Carey, Jason;Charpentier, Guillaume;Crenshaw, Andrew T.;Doney, Alex S. F.;Dorkhan, Mozhgan;Edkins, Sarah;Emilsson, Valur;Eury, Elodie;Forsen, Tom;Gertow, Karl;Gigante, Bruna;Grant, George B.;Groves, Christopher J.;Guiducci, Candace;Herder, Christian;Hreidarsson, Astradur B.;Hui, Jennie;James, Alan;Jonsson, Anna;Rathmann, Wolfgang;Klopp, Norman;Kravic, Jasmina;Krjutskov, Kaarel;Langford, Cordelia;Leander, Karin;Lindholm, Eero;Lobbens, Stephane;Mannisto, Satu;Mirza, Ghazala;Muehleisen, Thomas W.;Musk, Bill;Parkin, Melissa;Rallidis, Loukianos;Saramies, Jouko;Sennblad, Bengt;Shah, Sonia;Sigurdsson, Gunnar;Silveira, Angela;Steinbach, Gerald;Thorand, Barbara;Trakalo, Joseph;Veglia, Fabrizio;Wennauer, Roman;Winckler, Wendy;Zabaneh, Delilah;Campbell, Harry;van Duijn, Cornelia;Uitterlinden, Andre G.;Hofman, Albert;Sijbrands, Eric;Abecasis, Goncalo R.;Owen, Katharine R.;Zeggini, Eleftheria;Trip, Mieke D.;Forouhi, Nita G.;Syvanen, Ann-Christine;Eriksson, Johan G.;Peltonen, Leena;Noethen, Markus M.;Balkau, Beverley;Palmer, Colin N. A.;Lyssenko, Valeriya;Tuomi, Tiinamaija;Isomaa, Bo;Hunter, David J.;Qi, Lu;Shuldiner, Alan R.;Roden, Michael;Barroso, Ines;Wilsgaard, Tom;Beilby, John;Hovingh, Kees;Price, Jackie F.;Wilson, James F.;Rauramaa, Rainer;Lakka, Timo A.;Lind, Lars;Dedoussis, George;Njolstad, Inger;Pedersen, Nancy L.;Khaw, Kay-Tee;Wareham, Nicholas J.;Keinanen-Kiukaanniemi, Sirkka M.;Saaristo, Timo E.;Korpi-Hyovalti, Eeva;Saltevo, Juha;Laakso, Markku;Kuusisto, Johanna;Metspalu, Andres;Collins, Francis S.;Mohlke, Karen L.;Bergman, Richard N.;Tuomilehto, Jaakko;Boehm, Bernhard O.;Gieger, Christian;Hveem, Kristian;Cauchi, Stephane;Froguel, Philippe;Baldassarre, Damiano;Tremoli, Elena;Humphries, Steve E.;Saleheen, Danish;Danesh, John;Ingelsson, Erik;Ripatti, Samuli;Salomaa, Veikko;Erbel, Raimund;Joeckel, Karl-Heinz;Moebus, Susanne;Peters, Annette;Illig, Thomas;de Faire, Ulf;Hamsten, Anders;Morris, Andrew D.;Donnelly, Peter J.;Frayling, Timothy M.;Hattersley, Andrew T.;Boerwinkle, Eric;Melander, Olle;Kathiresan, Sekar;Nilsson, Peter M.;Deloukas, Panos;Thorsteinsdottir, Unnur;Groop, Leif C.;Stefansson, Kari;Hu, Frank;Pankow, James S.;Dupuis, Josee;Meigs, James B.;Altshuler, David;Boehnke, Michael;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
单胰腺β细胞在小鼠中共表达多种胰岛激素基因。
影响因子：
8.2
作者：
Katsuta, H.;Akashi, T.;Katsuta, R.;Nagaya, M.;Kim, D.;Arinobu, Y.;Hara, M.;Bonner-Weir, S.;Sharma, A. J.;Akashi, K.;Weir, G. C.
通讯作者：
Weir, G. C.