Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells.
Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells.
复制标题
DOI：
10.1016/j.molmet.2017.03.007
复制
发表时间：
2017-06
影响因子：
8.1
通讯作者：
Lickert H
中科院分区：
文献类型：
--
作者：
Bastidas-Ponce A;Roscioni SS;Burtscher I;Bader E;Sterr M;Bakhti M;Lickert H
转录因子Foxa 2和Pdx 1是β细胞发育和功能的关键调节因子。这些TF或其各自的顺式调节共有结合位点的突变已与青年成熟期糖尿病（MODY）、胰腺发育不全或人类糖尿病易感性相关联。虽然Foxa 2已被证明在小鼠胚胎发育过程中直接调节Pdx 1的表达，但这种基因调控相互作用对出生后β细胞成熟的影响仍然不清楚。为了方便地监测Foxa 2和Pdx 1的表达结构域并分析它们的功能互连，我们通过将先前描述的Foxa 2-Venus融合（FVF）与新产生的Pdx 1-BFP（蓝色荧光蛋白）融合（PBF）小鼠杂交来产生新的双敲入纯合（FVFPBFDHom）荧光报告基因小鼠模型。尽管成年PBF纯合子动物表现出Pdx 1表达水平的降低，但它们血糖正常。相反，尽管胰腺和内分泌发育正常，但FVFPBFDHom报告基因雄性动物在断奶时出现高血糖症，并显示胰岛中Pdx 1水平降低，这与β细胞数量和胰岛结构的改变一致。未能建立成熟β细胞导致β细胞身份的丧失和向其他内分泌细胞命运的转分化。进一步的分析表明，Foxa 2和Pdx 1在基因和功能上协同调节成体β细胞的成熟。我们的数据表明，胰腺β细胞的成熟需要Foxa 2和Pdx 1的协同作用。了解出生后β细胞成熟的基因调控网络将有助于解释糖尿病的病理机制，并确定再生去分化β细胞团的触发因素。荧光蛋白与Foxa 2和Pdx 1的融合诱导断奶时的高血糖。双敲入（FVFPBFDHom）报告基因动物表现出Pdx 1蛋白的低表达水平。FVFPBFDHom报告基因雄性小鼠显示β细胞成熟和功能受损。Foxa 2和Pdx 1的协同作用调节β细胞的出生后成熟
The transcription factors (TF) Foxa2 and Pdx1 are key regulators of beta-cell (β-cell) development and function. Mutations of these TFs or their respective cis-regulatory consensus binding sites have been linked to maturity diabetes of the young (MODY), pancreas agenesis, or diabetes susceptibility in human. Although Foxa2 has been shown to directly regulate Pdx1 expression during mouse embryonic development, the impact of this gene regulatory interaction on postnatal β-cell maturation remains obscure. In order to easily monitor the expression domains of Foxa2 and Pdx1 and analyze their functional interconnection, we generated a novel double knock-in homozygous (FVFPBFDHom) fluorescent reporter mouse model by crossing the previously described Foxa2-Venus fusion (FVF) with the newly generated Pdx1-BFP (blue fluorescent protein) fusion (PBF) mice. Although adult PBF homozygous animals exhibited a reduction in expression levels of Pdx1, they are normoglycemic. On the contrary, despite normal pancreas and endocrine development, the FVFPBFDHom reporter male animals developed hyperglycemia at weaning age and displayed a reduction in Pdx1 levels in islets, which coincided with alterations in β-cell number and islet architecture. The failure to establish mature β-cells resulted in loss of β-cell identity and trans-differentiation towards other endocrine cell fates. Further analysis suggested that Foxa2 and Pdx1 genetically and functionally cooperate to regulate maturation of adult β-cells. Our data show that the maturation of pancreatic β-cells requires the cooperative function of Foxa2 and Pdx1. Understanding the postnatal gene regulatory network of β-cell maturation will help to decipher pathomechanisms of diabetes and identify triggers to regenerate dedifferentiated β-cell mass. Fusion of fluorescent proteins to Foxa2 and Pdx1 induce hyperglycemia at weaning age. Double knock-in (FVFPBFDHom) reporter animals exhibit low expression levels of Pdx1 protein. FVFPBFDHom reporter male mice show impairment in β-cell maturation and function. Cooperative function of Foxa2 and Pdx1 regulates postnatal maturation of β-cells.