Abstract
The MAF family transcription factors are homologs of v-Maf, the oncogenic component of the avian retrovirus AS42. They are subdivided into 2 groups, small and large MAF proteins, according to their structure, function, and molecular size. MAFK is a member of the small MAF family and acts as a dominant negative form of large MAFs. In previous research we generated transgenic mice that overexpress MAFK in order to suppress the function of large MAF proteins in pancreatic β-cells. These mice developed hyperglycemia in adulthood due to impairment of glucose-stimulated insulin secretion. The aim of the current study is to examine the effects of β-cell-specific Mafk overexpression in endocrine cell development. The developing islets of Mafk-transgenic embryos appeared to be disorganized with an inversion of total numbers of insulin+ and glucagon+ cells due to reduced β-cell proliferation. Gene expression analysis by quantitative RT-PCR revealed decreased levels of β-cell-related genes whose expressions are known to be controlled by large MAF proteins. Additionally, these changes were accompanied with a significant increase in key β-cell transcription factors likely due to compensatory mechanisms that might have been activated in response to the β-cell loss. Finally, microarray comparison of gene expression profiles between wild-type and transgenic pancreata revealed alteration of some uncharacterized genes including Pcbd1, Fam132a, Cryba2, and Npy, which might play important roles during pancreatic endocrine development. Taken together, these results suggest that Mafk overexpression impairs endocrine development through a regulation of numerous β-cell-related genes. The microarray analysis provided a unique data set of differentially expressed genes that might contribute to a better understanding of the molecular basis that governs the development and function of endocrine pancreas.
Highlights
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, which eventually leads to a series of complications in various organs [1]
In type 2 diabetes (T2D), the peripheral tissues are resistant to insulin action and the disease is often accompanied by obesity and hyperlipidemia
In the islet of Mafa−/−;Mafk transgenic (Mafk-Tg) mice, the destructive changes were more severe compared to Mafa−/− mice [25]. These results suggest that the expression of Mafa during the neonatal period compensates for the effect of Mafk overexpression in embryos, which is consistent with a previous report showing the functional significances of Mafa after birth [33]
Summary
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, which eventually leads to a series of complications in various organs [1]. A subset of the pancreatic epithelial cells starts to express the proendocrine factor Ngn and gives rise to all types of endocrine cells [3,4,5,6]. During the secondary transition starting from around E13.5, the differentiating endocrine cells expand markedly, migrate into mesenchyme, and eventually aggregate to form Langerhans islets [7]. The expression of a cascade of different transcription factors stimulates the differentiation into distinct endocrine lineages. The expression of a cascade of different transcription factors stimulates the differentiation into distinct endocrine lineages. αcell-related transcription factors include Mafb, Nkx2.2, Pax, Foxa, Pou3f4, and Arx, whereas β-cell differentiation is controlled by Pdx, Mafb, Pax, Pax, Nkx2.2, and Nkx6.1 [8]
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