Transcriptional regulation of α-cell differentiation

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2011-10, Vol.13 (s1), p.13-20
• Main Authors: Bramswig, N. C., Kaestner, K. H.
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - physiology; Cell Differentiation; Cell fate; Developmental stages; Diabetes; Diabetes mellitus; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Embryonic Stem Cells; Forkhead protein; Gene Expression Regulation; Gene regulation; Glucagon-Secreting Cells - cytology; Glucagon-Secreting Cells - metabolism; Homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - physiology; Homeostasis; Humans; Insulin-Secreting Cells - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurogenins; pancreatogenesis; Pax6 protein; Regulatory Factor X Transcription Factors; Trans-Activators - genetics; Trans-Activators - physiology; Transcription factors; Transcription Factors - genetics; Transcription Factors - physiology; transcriptional regulation; transdifferentiation; α-cells
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2011.01440.x

The development of the endocrine pancreas and the differentiation of its five cell types, α, β, δ, ε and pancreatic polypeptide (PP) cells, are a highly complex and tightly regulated process. Proper differentiation and function of α‐ and β‐cells are critical for blood glucose homeostasis. These processes are governed by multiple transcription factors and other signalling systems, and its dysregulation results in diabetes. The differentiation of α‐cells and the maintenance of α‐cell function can be influenced at several stages during development and in the maturing islet. Many transcription factors, such as neurogenin 3 (Ngn3), pancreatic duodenal homeobox 1 (Pdx1) and regulatory factor x6 (Rfx6), play a crucial role in the determination of the endocrine cell fate, while other transcription factors, such as aristaless‐related homeobox (Arx) and forkhead box A2 (Foxa2), are implicated in the initial or terminal differentiation of α‐cells. In vivo and in vitro studies have shown that preproglucagon transcription, and therefore the maintenance of α‐cell function, is regulated by several factors, including forkhead box A1 (Foxa1), paired box 6 (Pax6), brain4 (Brn4) and islet‐1 (Isl‐1). Detailed information about the regulation of normal and abnormal α‐cell differentiation gives insight into the pathogenesis of diabetes, identifies further targets for diabetes treatment and provides clues for the reprogramming of α‐ to β‐cells for replacement therapy.