| First Author | Paul L | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 3 | Pages | 687-98 |
| PubMed ID | 26631740 | Mgi Jnum | J:246400 |
| Mgi Id | MGI:5923187 | Doi | 10.2337/db15-0713 |
| Citation | Paul L, et al. (2016) Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine beta-Cells. Diabetes 65(3):687-98 |
| abstractText | Transcription factor expression fluctuates during beta-cell ontogeny, and disruptions in this pattern can affect the development or function of those cells. Here we uncovered that murine endocrine pancreatic progenitors express high levels of the homeodomain transcription factor Prox1, whereas both immature and mature beta-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with beta-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature beta-cells has no functional consequences; in contrast, Prox1 overexpression in immature beta-cells promotes acute fasting hyperglycemia. Using a combination of immunostaining and quantitative and comparative gene expression analyses, we determined that Prox1 upregulation reduces proliferation, impairs maturation, and enables apoptosis in postnatal beta-cells. Also, we uncovered substantial deficiency in beta-cells that overexpress Prox1 of the key regulator of beta-cell maturation MafA, several MafA downstream targets required for glucose-stimulated insulin secretion, and genes encoding important components of FGF signaling. Moreover, knocking down PROX1 in human EndoC-betaH1 beta-cells caused increased expression of many of these same gene products. These and other results in our study indicate that reducing the expression of Prox1 is beneficial for the expansion and maturation of postnatal beta-cells. |
