Transcription profiling of pancreatic islets in wild type and Tcf-1 knock-out mice to identify target genes Tcf-1 that may be responsible of mediating beta cell growth

Mutations in several transcription factors lead to a subtype of type 2 diabetes called maturity-onset diabetes of the young (MODY), which are characterized by autosomal dominant inheritance, an early age of disease onset, and development of marked hyperglycemia with a progressive impairment in insulin secretion (Shih and Stoffel, 2002). The most frequent form of MODY is caused by mutations in the gene encoding hepatocyte nuclear factor-1a (HNF-1a, TCF1). Mutant mice with loss of Tcf1 function as well as transgenic mice expressing a naturally occurring dominant-negative form of human TCF1(P291fsinsC) in pancreatic beta cells develop progressive hyperglycemia due to impaired glucose-stimulated insulin secretion (Hagenfeldt-Johansson et al., 2001; Yamagata et al., 2002). Importantly, these mice exhibit a progressive reduction in beta cell number, proliferation rate, and pancreatic insulin content. These data indicate that Tcf-1 target genes are also required for maintenance of normal beta cell mass. In this study we sought to identify target genes of Tcf-1 that may be responsible of mediating beta cell growth by comparing gene expression profiles of Tcf-1 knock-out and wild-type littermates in isolated pancreatic islets.多种转录因子的突变可引发一类2型糖尿病亚型——青少年发病的成年型糖尿病（maturity-onset diabetes of the young, MODY），该疾病以常染色体显性遗传、早发起病、出现显著高血糖并伴进行性胰岛素分泌受损为特征（Shih and Stoffel, 2002）。MODY最常见的亚型由编码肝细胞核因子-1α（hepatocyte nuclear factor-1a, HNF-1α, TCF1）的基因突变所致。Tcf1功能缺失的突变小鼠，以及在胰腺β细胞中表达天然存在的显性负效人类TCF1（P291fsinsC）的转基因小鼠，均会因葡萄糖刺激的胰岛素分泌受损而出现进行性高血糖（Hagenfeldt-Johansson et al., 2001; Yamagata et al., 2002）。值得注意的是，此类小鼠的β细胞数量、增殖速率及胰腺胰岛素含量均呈进行性下降。上述结果表明，Tcf-1的靶基因同样是维持正常β细胞团块所必需的。本研究通过对比分离的胰腺胰岛中Tcf1敲除（knock-out）小鼠与其野生型同窝仔鼠的基因表达谱，旨在筛选出可能介导β细胞生长的Tcf-1靶基因。