MafA in B cell development and function

胰岛素在胰岛的β细胞中合成。葡萄糖的生理水平通过这种激素对外周组织的作用来维持，β细胞功能的缺陷导致糖尿病患者的高血糖症。近年来，已经收集到大量证据表明，富含胰岛的胰岛素基因转录调节因子不仅在β细胞功能中起重要作用，而且在发育过程中的β细胞形成中也起重要作用。我们实验室最近分离并显示MafA，一种含有碱性亮氨酸拉链的转录因子，是胰岛素基因表达的关键激活因子。该因子首先在胰腺器官发生期间β细胞形成的第二和主要阶段期间形成的胰岛素产生细胞中检测到，并且仅在胰腺内的胰岛β细胞中检测到。MafA的发育表达模式是新颖的，因为所有其他富含胰岛的转录因子在非激素和胰岛表达祖细胞中均被更早和广泛地诱导。基于MafA表达模式的独特性和其他密切相关的Maf蛋白在细胞分化过程中的贡献，我们认为MafA参与定义与β细胞身份相关的基因的表达。可以说，MafA是比胰岛素更好的功能性β细胞的标志物，因为在缺乏正常细胞功能所需的葡萄糖敏感蛋白的第一阶段细胞中也检测到激素表达。为了测试MafA对β细胞的重要性，我们计划：（1）确定MafA如何影响体内β细胞活性;（2）确定MafA活化如何在β细胞中调节;（3）确定MafA在β细胞中的转录靶点。这些研究将为MafA对β细胞的重要性提供更深入的了解，并可能提供将被广泛应用的信息。 在产生可接受的β样细胞用于1型和2型糖尿病的治疗性治疗中是有价值的。

Insulin is synthesized in beta cells of the islet of Langerhans. Physiological levels of glucose are maintained through the actions of this hormone on peripheral tissues, with defects in beta cell function resulting in hyperglycemia in diabetics. In recent years, substantial evidence has been collected demonstrating that islet-enriched transcriptional regulators of the insulin gene not only play an important role in beta cell function, but also in beta cell formation during development. Our laboratory recently isolated and showed that MafA, a basic leucine-zipper containing transcription factor, is a key activator of insulin gene expression. This factor is first detected in the insulin-producing cells formed during the second and predominant phase of beta cell formation during pancreatic organogenesis, and only in islet beta cells within the pancreas. The developmental expression pattern of MafA is novel, as all other islet-enriched transcription factors are induced earlier and broadly in both non-hormone and hormone-expressing progenitors. Based upon the uniqueness of the MafA expression pattern and the contribution of other closely related Maf proteins in cell differentiation processes, we believe that MafA is involved in defining the expression of genes associated with beta cell identity. Arguably, MafA is a better marker of functional beta cells than even insulin, as hormone expression is also detected in first phase cells that lack glucose-sensing proteins required for normal cell function. To test how significant MafA is to the beta cell, we plan to: (1) determine how MafA influences beta cell activity in vivo; (2) determine how MafA activation is regulated in beta cells; and (3) identify transcriptional targets of MafA in beta cells. These studies will provide greater insight into how fundamental MafA is to the beta cell, and likely provide information that will be valuable in generating acceptable beta-like cells for therapeutic treatment of type 1 and type 2 diabetics.