Koch Marta, Nicolas Maya, Zschaetzsch Marlen, de Geest Natalie, Claeys Annelies, Yan Jiekun, Morgan Matthew J, Erfurth Maria-Luise, Holt Matthew, Schmucker Dietmar, Hassan Bassem A
Laboratory of Neurogenetics, Center for Brain and Disease Research, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
Center for Human Genetics, University of Leuven School of Medicine, KU Leuven, Leuven, Belgium.
Front Cell Neurosci. 2018 Feb 8;11:416. doi: 10.3389/fncel.2017.00416. eCollection 2017.
Injury to the adult central nervous systems (CNS) can result in severe long-term disability because damaged CNS connections fail to regenerate after trauma. Identification of regulators that enhance the intrinsic growth capacity of severed axons is a first step to restore function. Here, we conducted a gain-of-function genetic screen in Drosophila to identify strong inducers of axonal growth after injury. We focus on a novel axis the Down Syndrome Cell Adhesion Molecule (Dscam1), the de-ubiquitinating enzyme Fat Facets (Faf)/Usp9x and the Jun N-Terminal Kinase (JNK) pathway transcription factor Kayak (Kay)/Fos. Genetic and biochemical analyses link these genes in a common signaling pathway whereby Faf stabilizes Dscam1 protein levels, by acting on the 3'-UTR of its mRNA, and Dscam1 acts upstream of the growth-promoting JNK signal. The mammalian homolog of Faf, Usp9x/FAM, shares both the regenerative and Dscam1 stabilizing activities, suggesting a conserved mechanism.
成年中枢神经系统（CNS）损伤可导致严重的长期残疾，因为受损的中枢神经系统连接在创伤后无法再生。识别增强切断轴突内在生长能力的调节因子是恢复功能的第一步。在这里，我们在果蝇中进行了功能获得性基因筛选，以识别损伤后轴突生长的强效诱导剂。我们关注一个新的轴，即唐氏综合征细胞粘附分子（Dscam1）、去泛素化酶Fat Facets（Faf）/Usp9x和Jun N端激酶（JNK）途径转录因子Kayak（Kay）/Fos。遗传和生化分析将这些基因联系在一个共同的信号通路中，其中Faf通过作用于其mRNA的3'-UTR来稳定Dscam1蛋白水平，而Dscam1在促进生长的JNK信号上游起作用。Faf的哺乳动物同源物Usp9x/FAM具有再生和稳定Dscam1的活性，这表明存在一种保守机制。
