Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine β-Cells.
Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine β-Cells.
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DOI：
10.2337/db15-0713
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发表时间：
2016-03
期刊：
影响因子：
7.7
通讯作者：
Sosa-Pineda B
中科院分区：
文献类型：
--
作者：
Paul L;Walker EM;Drosos Y;Cyphert HA;Neale G;Stein R;South J;Grosveld G;Herrera PL;Sosa-Pineda B
转录因子表达在β细胞个体发育期间波动，并且这种模式的破坏可以影响这些细胞的发育或功能。在这里，我们发现小鼠内分泌胰腺祖细胞表达高水平的同源结构域转录因子Prox 1，而未成熟和成熟的β细胞几乎不表达这种蛋白质。我们还研究了持续的Prox 1表达是否与使用转基因小鼠方法的β细胞发育或维持不相容。我们发现，成熟β细胞中Prox 1的上调没有功能性后果;相反，未成熟β细胞中Prox 1的过表达促进急性空腹高血糖症。使用免疫染色和定量和比较基因表达分析的组合，我们确定Prox 1上调减少增殖，损害成熟，并使出生后β细胞凋亡。此外，我们发现β细胞过度表达β细胞成熟MafA的关键调节因子Prox 1，葡萄糖刺激胰岛素分泌所需的几个MafA下游靶点，以及编码FGF信号传导重要组分的基因的实质性缺陷。此外，敲低人EndoC-βH1 β细胞中的PROX 1可导致许多相同基因产物的表达增加。我们研究中的这些和其他结果表明，减少Prox 1的表达有利于出生后β细胞的扩增和成熟。
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.