The Lysosomal Transcription Factor TFEB Represses Myelination Downstream of the Rag-Ragulator Complex.
The Lysosomal Transcription Factor TFEB Represses Myelination Downstream of the Rag-Ragulator Complex.
复制标题
DOI：
10.1016/j.devcel.2018.10.003
复制
发表时间：
2018-11-05
影响因子：
11.8
通讯作者：
Talbot WS
中科院分区：
文献类型：
--
作者：
Meireles AM;Shen K;Zoupi L;Iyer H;Bouchard EL;Williams A;Talbot WS
髓鞘允许快速和有效的轴突传导，但仍有许多关于髓鞘形成的调节机制有待确定。为了研究髓鞘形成的遗传基础，我们使用斑马鱼进行了遗传筛选。在这里，我们表明，溶酶体G蛋白RagA是必不可少的中枢神经系统髓鞘。在rraga−/−突变型少突胶质细胞中，溶酶体转录因子Tfeb的靶基因上调，这与之前RagA抑制Tfeb活性的证据一致。Tfeb功能的丧失足以恢复RagA突变体的髓鞘形成，表明过度活跃的Tfeb抑制髓鞘形成。相反，tfeb−/−单突变体表现出异位髓鞘，进一步表明Tfeb在发育过程中抑制髓鞘形成。在脱髓鞘和髓鞘再生的小鼠模型中，TFEB表达在少突胶质细胞中增加，但该蛋白质定位于细胞质，因此不活跃，特别是在髓鞘再生期间。这些结果定义了髓鞘形成的基本调节因子，并可能推进治疗髓鞘再生的方法。Meireles，Shen等人在斑马鱼中使用遗传方法表明，溶酶体调节剂RagA和Tfeb在调节髓鞘形成方面具有相反的作用。Tfeb抑制髓鞘形成，RagA抑制Tfeb。在RagA突变体中，Tfeb过度活跃，髓磷脂几乎被消除。
Myelin allows for fast and efficient axonal conduction, but much remains to be determined about the mechanisms that regulate myelin formation. To investigate the genetic basis of myelination, we carried out a genetic screen using zebrafish. Here we show that the lysosomal Gprotein RagA is essential for CNS myelination. In rraga−/− mutant oligodendrocytes, target genes of the lysosomal transcription factor Tfeb are upregulated, consistent with previous evidence that RagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore myelination in RagA mutants, indicating that hyperactive Tfeb represses myelination. Conversely, tfeb−/− single mutants exhibit ectopic myelin, further indicating that Tfeb represses myelination during development. In a mouse model of de- and remyelination, TFEB expression is increased in oligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especially during remyelination. These results define essential regulators of myelination and may advance approaches to therapeutic remyelination. Using genetic approaches in zebrafish, Meireles, Shen et al. shows that the lysosomal regulators RagA and Tfeb have opposing roles to regulate myelin formation. Tfeb represses myelination, and RagA represses Tfeb. In RagA mutants, Tfeb is hyperactive and myelin is nearly eliminated.
登录
查看更多内容
影响因子：
20.1
作者：
Ding Y;Sun X;Huang W;Hoage T;Redfield M;Kushwaha S;Sivasubbu S;Lin X;Ekker S;Xu X
通讯作者：
Xu X
影响因子：
7.5
作者：
Ferguson SM
通讯作者：
Ferguson SM
影响因子：
11.8
作者：
Medina, Diego L.;Fraldi, Alessandro;Bouche, Valentina;Annunziata, Fabio;Mansueto, Gelsomina;Spampanato, Carmine;Puri, Claudia;Pignata, Antonella;Martina, Jose A.;Sardiello, Marco;Palmieri, Michela;Polishchuk, Roman;Puertollano, Rosa;Ballabio, Andrea
通讯作者：
Ballabio, Andrea
影响因子：
64.8
作者：
Fuenfschilling, Ursula;Supplie, Lotti M.;Mahad, Don;Boretius, Susann;Saab, Aiman S.;Edgar, Julia;Brinkmann, Bastian G.;Kassmann, Celia M.;Tzvetanova, Iva D.;Moebius, Wiebke;Diaz, Francisca;Meijer, Dies;Suter, Ueli;Hamprecht, Bernd;Sereda, Michael W.;Moraes, Carlos T.;Frahm, Jens;Goebbels, Sandra;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin
DOI：
10.1083/jcb.201209135
发表时间：
2013-02-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Martina JA;Puertollano R
通讯作者：
Puertollano R