Abstract
The postnatal proliferation and maturation of insulin-secreting pancreatic β-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional β-cells. Maturation of β-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for β-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or β-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of β-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of β-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of β-cells via prolactin signaling.
Highlights
Accumulating evidence suggests that postnatal organ development and maturation are critical for future health, especially with respect to metabolic disease [1]
Several genes that were downregulated in musculoaponeurotic fibrosarcoma oncogene family protein A (MafA) KO islets, along with several molecules critical for b-cell function, were examined in mouse bcell line MIN6 cells that were transfected with MafA siRNA and MIN6 cells that were transfected with control siRNA
The results revealed the downstream candidates of MafA, and prolactin receptor (Prlr) was a focus of this study
Summary
Accumulating evidence suggests that postnatal organ development and maturation are critical for future health, especially with respect to metabolic disease [1]. The compensatory growth of b-cell mass in insulin resistance has been intensively investigated [4], the signaling pathway that regulates postnatal proliferation of b-cells is less well known [5]. Uncovering this mechanism will elucidate how b-cell mass is regulated during development and how the insulin-expressing cells that differentiate from stem cells acquire the capacity to proliferate. Prolactin signaling may be involved in the proliferation of b-cells after birth, as Prlr knockout (KO) neonates have reduced b-cell mass [8]
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