Department of Cell Biology & Anatomy, LSU Health Sciences Center, MEB 6A12, 1901 Perdido Street, New Orleans, LA 70112, USA.
Development. 2010 Apr;137(7):1107-16. doi: 10.1242/dev.046045.
The RNA-binding protein Bicaudal C is an important regulator of embryonic development in C. elegans, Drosophila and Xenopus. In mouse, bicaudal C (Bicc1) mutants are characterized by the formation of fluid-filled cysts in the kidney and by expansion of epithelial ducts in liver and pancreas. This phenotype is reminiscent of human forms of polycystic kidney disease (PKD). Here, we now provide data that Bicc1 functions by modulating the expression of polycystin 2 (Pkd2), a member of the transient receptor potential (TRP) superfamily. Molecular analyses demonstrate that Bicc1 acts as a post-transcriptional regulator upstream of Pkd2. It regulates the stability of Pkd2 mRNA and its translation efficiency. Bicc1 antagonized the repressive activity of the miR-17 microRNA family on the 3'UTR of Pkd2 mRNA. This was substantiated in Xenopus, in which the pronephric defects of bicc1 knockdowns were rescued by reducing miR-17 activity. At the cellular level, Bicc1 protein is localized to cytoplasmic foci that are positive for the P-body markers GW182 and HEDLs. Based on these data, we propose that the kidney phenotype in Bicc1(-/-) mutant mice is caused by dysregulation of a microRNA-based translational control mechanism.
RNA 结合蛋白 Bicaudal C 是秀丽隐杆线虫、果蝇和非洲爪蟾胚胎发育的重要调节因子。在小鼠中，bicaudal C（Bicc1）突变体的特征是肾脏中形成充满液体的囊肿，以及肝脏和胰腺中上皮导管扩张。这种表型让人联想到人类多囊肾病（PKD）的形式。在这里，我们现在提供的数据表明，Bicc1 通过调节多囊蛋白 2（Pkd2）的表达起作用，Pkd2 是瞬时受体电位（TRP）超家族的成员。分子分析表明，Bicc1 作为 Pkd2 的转录后调节剂发挥作用。它调节 Pkd2 mRNA 的稳定性及其翻译效率。Bicc1 拮抗 miR-17 微 RNA 家族对 Pkd2 mRNA 3'UTR 的抑制活性。这在非洲爪蟾中得到了证实，其中 bicc1 敲低的前肾缺陷可以通过降低 miR-17 的活性来挽救。在细胞水平上，Bicc1 蛋白定位于细胞质焦点，这些焦点对 P 体标记物 GW182 和 HEDLs 呈阳性。基于这些数据，我们提出 Bicc1(-/-) 突变小鼠肾脏表型是由 microRNA 为基础的翻译控制机制失调引起的。
