Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine β-Cells.

Paul L, Walker EM, Drosos Y, Cyphert HA, Neale G, Stein R, South J, Grosveld G, Herrera PL, Sosa-Pineda B
Diabetes. 2016 65 (3): 687-98

PMID: 26631740 · PMCID: PMC4764148 · DOI:10.2337/db15-0713

Transcription factor expression fluctuates during β-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 β-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with β-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature β-cells has no functional consequences; in contrast, Prox1 overexpression in immature β-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 β-cells. Also, we uncovered substantial deficiency in β-cells that overexpress Prox1 of the key regulator of β-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-βH1 β-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 β-cells.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

MeSH Terms (23)

Animals Animals, Newborn Cell Differentiation Cell Line Cell Proliferation Chromatin Immunoprecipitation Computer Simulation Down-Regulation Enzyme-Linked Immunosorbent Assay Gene Expression Profiling Gene Knockdown Techniques Glucose Tolerance Test Homeodomain Proteins Humans Hyperglycemia Insulin Insulin-Secreting Cells Maf Transcription Factors, Large Mice Mice, Transgenic Real-Time Polymerase Chain Reaction RNA, Messenger Tumor Suppressor Proteins

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