Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; Insect Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho,Kamigyo-ku, Kyoto 602-8566, Japan.
Exp Cell Res. 2014 Aug 1;326(1):36-45. doi: 10.1016/j.yexcr.2014.06.004. Epub 2014 Jun 11.
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular weakness. Fused in Sarcoma (FUS) that has been identified in familial ALS is an RNA binding protein that is normally localized in the nucleus. However, its function in vivo is not fully understood. Drosophila has Cabeza (Caz) as a FUS homologue and specific knockdown of Caz in the eye imaginal disc and pupal retina using a GMR-GAL4 driver was here found to induce an abnormal morphology of the adult compound eyes, a rough eye phenotype. This was partially suppressed by expression of the apoptosis inhibitor P35. Knockdown of Caz exerted no apparent effect on differentiation of photoreceptor cells. However, immunostaining with an antibody to Cut that marks cone cells revealed fusion of these and ommatidia of pupal retinae. These results indicate that Caz knockdown induces apoptosis and also inhibits differentiation of cone cells, resulting in abnormal eye morphology in adults. Mutation in EGFR pathway-related genes, such as rhomboid-1, rhomboid-3 and mirror suppressed the rough eye phenotype induced by Caz knockdown. Moreover, the rhomboid-1 mutation rescued the fusion of cone cells and ommatidia observed in Caz knockdown flies. The results suggest that Caz negatively regulates the EGFR signaling pathway required for determination of cone cell fate in Drosophila.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，导致进行性肌肉无力。融合肉瘤（FUS）已在家族性 ALS 中被鉴定出来，是一种 RNA 结合蛋白，正常定位于细胞核内。然而，其在体内的功能尚未完全了解。果蝇具有 Cabeza（Caz）作为 FUS 的同源物，使用 GMR-GAL4 驱动子特异性敲低眼盘和蛹视网膜中的 Caz，发现会诱导成年复眼的异常形态，即粗糙眼表型。这种表型部分被凋亡抑制剂 P35 的表达所抑制。Caz 的敲低对感光细胞的分化没有明显影响。然而，用标记锥细胞的 Cut 抗体进行免疫染色显示，这些细胞与蛹视网膜的小眼融合。这些结果表明，Caz 敲低诱导细胞凋亡，并抑制锥细胞的分化，导致成虫眼睛形态异常。EGFR 途径相关基因的突变，如 rhomboid-1、rhomboid-3 和 mirror，抑制了 Caz 敲低诱导的粗糙眼表型。此外，rhomboid-1 突变挽救了在 Caz 敲低果蝇中观察到的锥细胞和小眼的融合。结果表明，Caz 负调控 EGFR 信号通路，该通路对果蝇中锥细胞命运的决定是必需的。
