Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine ß-Cells.
Diabetes
; 65(3): 687-98, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26631740
ABSTRACT
Transcription factor expression fluctuates during ß-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 ß-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with ß-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature ß-cells has no functional consequences; in contrast, Prox1 overexpression in immature ß-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 ß-cells. Also, we uncovered substantial deficiency in ß-cells that overexpress Prox1 of the key regulator of ß-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-ßH1 ß-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 ß-cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
RNA Mensageiro
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Diferenciação Celular
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Proteínas de Homeodomínio
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Proteínas Supressoras de Tumor
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Proliferação de Células
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Células Secretoras de Insulina
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Fatores de Transcrição Maf Maior
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Hiperglicemia
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Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article