Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
J Genet Genomics. 2011 Jan;38(1):1-11. doi: 10.1016/j.jcg.2010.12.004.
TRIpartite Motif (TRIM) family proteins are ring finger domain-containing, multi-domain proteins implicated in many biological processes. Members of the TRIM-9/C-I subfamily of TRIM proteins, including TRIM-9, MID1 and MID2, have neuronal functions and are associated with neurological diseases. To explore whether the functions of C-I TRIM proteins are conserved in invertebrates, we analyzed Caenorhabditis elegans and Drosophila trim-9 mutants. C. elegans trim-9 mutants exhibit defects in the ventral guidance of hermaphrodite specific neuron (HSN) and the touch neuron AVM. Further genetic analyses indicate that TRIM-9 participates in the UNC-6-UNC-40 attraction pathway. Asymmetric distribution of UNC-40 during HSN development is normal in trim-9 mutants. However, the asymmetric localization of MIG-10, a downstream effector of UNC-40, is abolished in trim-9 mutants. These results suggest that TRIM-9 functions upstream of MIG-10 in the UNC-40 pathway. Moreover, we showed that TRIM-9 exhibits E3 ubiquitin ligase activity in vitro and this activity is important for TRIM-9 function in vivo. Additionally, we found that Drosophila trim-9 is required for the midline attraction of a group of sensory neuron axons. Over-expression of the Netrin/UNC-6 receptor Frazzled suppresses the guidance defects in trim-9 mutants. Our study reveals an evolutionarily conserved function of TRIM-9 in the UNC-40/Frazzled-mediated UNC-6/Netrin attraction pathway.
TRIpartite Motif (TRIM) 家族蛋白是具有指环指结构域的多结构域蛋白，涉及许多生物学过程。TRIM 蛋白的 TRIM-9/C-I 亚家族成员，包括 TRIM-9、MID1 和 MID2，具有神经元功能，与神经疾病有关。为了探索 C-I TRIM 蛋白的功能是否在无脊椎动物中保守，我们分析了秀丽隐杆线虫和果蝇的 trim-9 突变体。秀丽隐杆线虫 trim-9 突变体在雌雄同体特异性神经元（HSN）和触觉神经元 AVM 的腹侧导向中表现出缺陷。进一步的遗传分析表明，TRIM-9 参与了 UNC-6-UNC-40 吸引途径。在 trim-9 突变体中，HSN 发育过程中 UNC-40 的不对称分布正常。然而，UNC-40 的下游效应物 MIG-10 的不对称定位在 trim-9 突变体中被消除。这些结果表明，TRIM-9 在 UNC-40 途径中作为 MIG-10 的上游因子发挥作用。此外，我们表明 TRIM-9 在体外具有 E3 泛素连接酶活性，并且这种活性对于 TRIM-9 在体内的功能很重要。此外，我们发现果蝇 trim-9 对于一组感觉神经元轴突的中线吸引是必需的。Netrin/UNC-6 受体 Frazzled 的过表达可抑制 trim-9 突变体的导向缺陷。我们的研究揭示了 TRIM-9 在 UNC-40/Frazzled 介导的 UNC-6/Netrin 吸引途径中的一个进化保守的功能。
