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.

Identify target genes of Tcf1 (Hnf1 alpha, MODY3), that may be responsible of mediating beta cell growth. See also a related paper by Fukui et al. and commentary.

Gene expression profiles of Tcf1 -/- and wild-type littermates in isolated pancreatic islets were compared using Affymetrix MG_U74A v2 arrays. Two replicates were independently analyzed (deposited at GEO-NCBI under accession number GSE3544).

Microarray analysis led to the identification of a transcript encoding transmembrane protein-27 (Tmem27) that is markedly reduced in pancreatic islets of Tcf-1 -/- mice compared to controls. This result was confirmed by RT-PCR in an independent group of animals. Promoter analysis and chromatin immunoprecipitation demonstrate that Tcf1 binds to conserved TCF1 binding sites in the Tmem27 promoter and that it activates transcription of this gene. Biochemical analysis determined that Tmem27 is a cell surface glycosylated protein. Tmem27 is expressed in hormone-positive cells throughout development but becomes restricted to pancreatic beta cells in the postnatal period. Tmem27 is essential for optimal beta cell growth in vitro and transgenic mice overexpressing Tmem27 exhibit increased islet mass.

Tmem27 (collectrin) is a Tcf1/Hnf1 alpha target and pancreatic beta cell transmembrane protein that regulates cell growth of pancreatic islets.

• beta cell proliferation: 1790, 2541, 3465, 3735, 3815,
• Hnf1a: 2541, 2929,