αE-Catenin as a Gatekeeper of β-Cell Identity and Growth

Abstract

The pancreas is a vital organ that serves dual roles in digestion and metabolic regulation. Its exocrine compartment secretes digestive enzymes and bicarbonate into the duodenum, while its endocrine compartment - organized into the islets of Langerhans - produces hormones including insulin, glucagon, and somatostatin to regulate blood glucose and energy homeostasis. Both compartments arise during embryogenesis from a common pool of multipotent progenitor cells, whose fate decisions are orchestrated by key developmental signaling pathways, including Wnt and Sonic Hedgehog (SHH), that coordinate the sequential emergence of exocrine, ductal, and endocrine cell lineages including insulin-producing β-cells, glucagon-producing α-cells, and somatostatin-producing δ-cells. αE-catenin is a critical regulator of cell adhesion and intracellular signaling that has emerged as an important modulator of pancreatic cell fate. Prior work from our group demonstrated that loss of αE-catenin in early multipotent pancreatic progenitors aberrantly activates SHH signaling, resulting in a failure of progenitor cells to exit the progenitor state and commit to endocrine differentiation. Building on this, we investigated whether αE-catenin continues to play a regulatory role later in development, specifically within maturing β-cells at the stage when insulin expression is first initiated. We found that deleting αE-catenin specifically in developing β-cells leads to a striking expansion of β-cell mass driven by increased proliferation, as well as molecular evidence of endocrine lineage instability and enhanced cellular plasticity. These effects were also observed in human islets, underscoring the translational relevance of our findings. Collectively, this work positions αE-catenin as a key regulator of β-cell homeostasis and identity and suggests that modulating this pathway could offer new strategies for promoting islet regeneration and expansion in the treatment of diabetes.