The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

Abstract

Paired box 4 (PAX4) is a key factor in the generation of insulin producing beta-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of beta-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates beta-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining beta-cells in parallel to the stimulation of their proliferation to replenish the beta-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action.