The circadian gene Arntl2 on distal mouse chromosome 6 controls thymocyte apoptosis.
Nonobese diabetic (NOD) mice are a model for type 1 diabetes that displays defects in central immune tolerance, including impairment of thymocyte apoptosis and proliferation. Thymocyte apoptosis is decreased in NOD/Lt mice compared to nondiabetic C3H/HeJ and C57BL/6 mice. Analysis of a set of NOD.C3H and NOD.B6 congenic mouse strains for distal chromosome 6 localizes the phenotype to the 700 kb Idd6.3 interval. Idd6.3 contains the type 1 diabetes candidate gene aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2), encoding a circadian rhythm-related transcription factor. Newly generated Arntl2-/-mouse strains reveal that inactivation of the B6 allele of Arntl2 is sufficient to both decrease thymocyte apoptosis and proliferation. When expressed from C3H or B6 alleles, ARNTL2 inhibits the transcription of interleukin 21 (Il21), a major player in the regulation of immune responses. IL-21 injection abolishes the B6 allele-mediated decrease of apoptosis and proliferation. Interestingly, IL-21 also leads to an increase in thymic proinflammatory Th17 helper cells. Our results identify Arntl2 as a gene controlling thymocyte apoptosis and proliferation along with Th17 development through the IL-21 pathway.
Mouse Molecular Genetics Laboratory, CNRS URA 2578, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France.|University Pierre and Marie Curie, Cellule Pasteur UPMC, 25 rue du Docteur Roux, 75015, Paris, France.
Basile
B
Lebailly
Mouse Genetics Engineering Center, CNRS URA 2578, Institut Pasteur, 28 rue du Docteur Roux, 75015, Paris, France.
Francina
F
Langa
Inserm U1016 - CNRS UMR8104, Groupe Hospitalier Cochin, Université Paris Descartes, 123 boulevard Port-Royal, 75014, Paris, France.
Christian
C
Boitard
Mouse Molecular Genetics Laboratory, CNRS URA 2578, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France.
Philip
P
Avner
Mouse Molecular Genetics Laboratory, CNRS URA 2578, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France. ute.rogner@inserm.fr.|Inserm U1016 - CNRS UMR8104, Groupe Hospitalier Cochin, Université Paris Descartes, 123 boulevard Port-Royal, 75014, Paris, France. ute.rogner@inserm.fr.
Ute Christine
UC
Rogner
D056930:ARNTL Transcription Factors / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002875:Chromosomes / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics; D018345:Mice, Knockout; D058504:Th17 Cells / Q000378:metabolism; D060168:Thymocytes / Q000378:metabolism / Q000473:pathology; D000098546:Interleukin-21
D056930:ARNTL Transcription Factors; C431792:Arntl2 protein, mouse; D007378:Interleukins; D000098546:Interleukin-21
Genomics. 1995 Aug 10;28(3):398-404
7490073
Diabetes. 2014 Jun;63(6):2148-57
24520124
J Immunol. 2007 Jan 15;178(2):732-9
17202333
J Exp Med. 2012 Mar 12;209(3):623-37
22329992
Genomics. 2001 Jun 1;74(2):163-71
11386752
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14028-33
18779574
PLoS One. 2013 Sep 02;8(9):e72801
24023776
Clin Exp Pharmacol Physiol. 2010 Dec;37(12):1154-8
20880188
Immunogenetics. 2007 May;59(5):407-16
17353998
Immunogenetics. 2010 Sep;62(9):585-92
20676886
J Autoimmun. 2005 Feb;24(1):11-23
15725572
Int Immunol. 1994 Feb;6(2):339-45
8155606
J Immunol. 2001 Feb 15;166(4):2404-11
11160299
Blood. 2013 Jan 3;121(1):107-17
23043071
Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19438-43
19880748
Diabetes. 2009 May;58(5):1144-55
19208913
Hum Mol Genet. 2006 Sep 15;15(18):2732-42
16893914
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D544-9
15608258
Diabetes. 2006 Jan;55(1):186-92
16380492
Blood. 2007 May 15;109(10):4135-42
17234735
J Biol Chem. 2007 Nov 30;282(48):34605-10
17884812
Diabetes. 2003 Jul;52(7):1677-82
12829632
Trends Immunol. 2008 Jun;29(6):290-4
18440864
Diabetes. 2011 Mar;60(3):867-75
21357471
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W452-7
22689647
Genome Res. 2001 May;11(5):863-74
11337480
J Leukoc Biol. 2007 Sep;82(3):645-56
17554014
J Immunol. 2005 Feb 15;174(4):2167-73
15699148
Diabetologia. 2001 Aug;44(8):1054-61
11484085
RNA. 2003 Apr;9(4):493-501
12649500
Immunol Cell Biol. 2007 Oct;85(7):503-5
17768419
Mol Immunol. 2010 Mar;47(6):1262-8
20080304
Nat Struct Mol Biol. 2015 Jun;22(6):476-484
25961797
Cancer Immunol Immunother. 2008 Oct;57(10):1439-49
18286285
J Immunol. 2004 Nov 1;173(9):5361-71
15494482
Nat Rev Drug Discov. 2014 May;13(5):379-95
24751819