Beyond association: A functional role for Tcf7l2 in β-cell development☆

Tcf7l2, also known as Tcf4, is a member of the HMG-box containing T-cell factor (Tcf)/Lymphoid enhancer factor (Lef) transcription factor family of DNA binding proteins downstream of the canonical Wnt pathway [1]. In addition to its well known role during development recent evidence suggests that the Wnt pathway is implicated in stem cell homeostasis, cancer development and metabolic disorders [2]. Thus, it is not surprising, that genome wide association studies (GWAS) have identified TCF7L2 as a locus conveying an increased risk for developing type 2 diabetes (T2D) for the homozygous carrier of the minor allele [3]. Since this finding, several studies have focused on understanding the mechanism underlying the metabolic function of Tcf7l2 in organs and in pancreatic b-cells. In the small intestine, Tcf7l2-dependent Wnt signaling is essential for maintenance of proliferating cells located in the “intervillus pockets” as well as for the differentiation towards the hormone-producing enteroendocrine lineage [2]. In these cells, Tcf7l2 regulates pro-glucagon expression, precursor of glucagon-derived hormones. In the adult pancreas, cumulative evidence suggests that Tcf7l2/b-catenin signaling is critical for Glucagon-like peptide 1 (Glp-1) induced b-cell proliferation and Stromal-derived factor 1 (Sdf-1)-mediated b-cell survival [4]. Moreover, recent data indicate that alternative splicing isoforms of TCF7L2 differently regulate b-cell proliferation and glucose-dependent insulin secretion in adult human islets [5]. Despite all these efforts, many questions remain, e.g. which metabolic organ requires Wnt/Tcf7l2 signaling for its function, when is Tcf7l2 function required for organ development and homeostasis, and is Tcf7l2 function conserved between the pre-clinical mouse model and human patients? Answers to these questions will unravel the contribution of TCF7L2 to the development of diabetes. In the April 2015 issue of Molecular Metabolism, Shao et al. provide new insight on the function of TCF7L2 in pancreatic b-cells [6]. The authors used an adenoviral vector system expressing a dominantnegative (DN) variant of TCF7L2 (TCF7L2DN) to attenuate canonical WNT/b-catenin signaling in insulinoma cells (Ins-1) and during pancreas development as well as in the adult islet. Specifically, forced