Gene expression profiles define a key checkpoint for type 1 diabetes in NOD mice.
cDNA microarrays with >11,000 cDNA clones from an NOD spleen cDNA library were used to identify temporal gene expression changes in NOD mice (1-10 weeks), which spontaneously develop type 1 diabetes, and changes between NOD and NOD congenic mice (NOD.Idd3/Idd10 and NOD.B10Sn-H2(b)), which have near zero incidence of insulitis and diabetes. The expression profiles identified two distinct groups of mice corresponding to an immature (1-4 weeks) and mature (6-10 weeks) state. The rapid switch of gene expression occurring around 5 weeks of age defines a key immunological checkpoint. Sixty-two known genes are upregulated, and 18 are downregulated at this checkpoint in the NOD. The expression profiles are consistent with increased antibody production, antigen presentation, and cell proliferation associated with an active autoimmune response. Seven of these genes map to confirmed diabetes susceptibility regions. Of these seven, three are excellent candidate genes not previously implicated in type 1 diabetes. Ten genes are differentially expressed between the NOD and congenic NOD at the immature stage (Hspa8, Hif1a, and several involved in cellular functions), while the other 70 genes exhibit expression differences during the mature (6-10 week) stage, suggesting that the expression differences of a small number of genes before onset of insulitis determine the disease progression.
Eckenrode
Sarah E
SE
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, Georgia, USA.
Ruan
Qingguo
Q
Yang
Ping
P
Zheng
Weipeng
W
McIndoe
Richard A
RA
She
Jin-Xiong
JX
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004798:Enzymes / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics
D017931:DNA Primers; D004798:Enzymes; D011506:Proteins