PLAGL1/ZAC, a Transient Neonatal Diabetes Mellitus Locus Gene, in Pancreatic beta-Cell Development and Function

Studies on congenital disorders of the pancreas have contributed to the identification of genes that are critical in β-cell development and function. Transient neonatal diabetes mellitus (TNDM) is a rare congenital disorder of the pancreas. It involves severe insulin deficiency at birth that reverses over weeks or months but may relapse with diabetes in later life. PLAGL1 (pleiomorphic a&barbelow;denoma g&barbelow;ene-l&barbelow;ike 1, also known as ZAC, zinc finger protein that regulates apoptosis and cell cycle arrest, and LOT1, Lost On Transformation 1) is one of the two possible genes at the TNDM locus and the multiple functions of PLAGL1/ZAC strongly suggest it as the causative gene of TNDM. We hypothesized that double dose expression of PLAGL1/ZAC impairs both β-cell development and function. To test this hypothesis, we began with the study of ZAC ontogeny. In developing human pancreas, ZAC is expressed with considerable specificity in differentiated β-cells, and its expression decreases dramatically from the second trimester to adult. These results imply a role of ZAC in a critical time window in β-cell development, supporting its role in TNDM and explaining the transient nature of the TNDM. In vitro, effects of ZAC overexpression on β-cell function was observed in INS-1 cells by using tetracycline regulatable system. Overexpression of ZAC inhibits glucose-stimulated insulin exocytosis and proinsulin biosynthesis. Glucose was found to be able to downregulate Lot1/ZAC1 expression in INS-1 cells and mouse islets. These data suggest ZAC as a negative regulator in some glucose-regulated pathways whose abnormally high level impairs β-cell function that explains the relapse of diabetes in TNDM. Finally, a gene expression profile study of INS-1 cells with or without induced ZAC expression identified STC1, IGF1R, SNAP25, GRP78, and P58IPK as possible targets of ZAC that mediate β-cell dysfunctions. CRABP2, strongly upregulated by ZAC, together with G0S2, GADD45α, and FHL2, may mediate ZAC function in both normal β-cell development and TNDM pathophysiology. In general, these studies suggest that tightly controlled expression level of ZAC is critical for β-cell development and function. It provides strong evidence that ZAC overexpression causes TNDM. In addition, two previously unstudied genes, STC1 and CRABP2, are suggested to play potential important roles in β-cell function and development.