Kim Kevin, Hung Ruei-Jiun, Perrimon Norbert
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Dev Cell. 2017 Jan 9;40(1):23-36. doi: 10.1016/j.devcel.2016.11.023. Epub 2016 Dec 22.
Proper regulation of osmotic balance and response to tissue damage is crucial in maintaining intestinal stem cell (ISC) homeostasis. We found that Drosophila miR-263a downregulates the expression of epithelial sodium channel (ENaC) subunits in enterocytes (ECs) to maintain osmotic and ISC homeostasis. In the absence of miR-263a, the intraluminal surface of the intestine displays dehydration-like phenotypes, Na levels are increased in ECs, stress pathways are activated in ECs, and ISCs overproliferate. Furthermore, miR-263a mutants have increased bacterial load and expression of antimicrobial peptides. Strikingly, these phenotypes are reminiscent of the pathophysiology of cystic fibrosis (CF) in which loss-of-function mutations in the chloride channel CF transmembrane conductance regulator can elevate the activity of ENaC, suggesting that Drosophila could be used as a model for CF. Finally, we provide evidence that overexpression of miR-183, the human ortholog of miR-263a, can also directly target the expressions of all three subunits of human ENaC.
正确调节渗透平衡以及对组织损伤作出反应对于维持肠道干细胞（ISC）的稳态至关重要。我们发现果蝇的miR-263a可下调肠细胞（EC）中上皮钠通道（ENaC）亚基的表达，以维持渗透压和ISC的稳态。在缺乏miR-263a的情况下，肠道腔内表面呈现出类似脱水的表型，肠细胞中的钠水平升高，肠细胞中的应激途径被激活，并且ISC过度增殖。此外，miR-263a突变体的细菌载量和抗菌肽表达增加。引人注目的是，这些表型让人联想到囊性纤维化（CF）的病理生理学，其中氯离子通道CF跨膜电导调节因子的功能丧失突变可提高ENaC的活性，这表明果蝇可作为CF的模型。最后，我们提供证据表明，miR-263a的人类同源物miR-183的过表达也可直接靶向人类ENaC所有三个亚基的表达。
