Cd59 and inflammation regulate Schwann cell development.
Cd59 and inflammation regulate Schwann cell development.
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DOI：
10.7554/elife.76640
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发表时间：
2022-06-24
期刊：
影响因子：
7.7
通讯作者：
Kucenas, Sarah
中科院分区：
文献类型：
--
作者：
Wiltbank, Ashtyn T.;Steisnon, Emma R.;Criswell, Stacey J.;Piller, Melanie;Kucenas, Sarah
有效的神经传递是生物体生存所必需的，并通过髓鞘形成增强。然而，调控髓磷脂和髓鞘胶质细胞发育的基因尚未完全表征。来自我们实验室和其他实验室的数据表明，编码gpi锚定小糖蛋白的cd59在发育中的斑马鱼、啮齿动物和人类少突胶质细胞（OLs）和雪旺细胞（SCs）中高度表达，并且cd59功能障碍的患者在儿童早期出现神经功能障碍。然而，Cd59在发育中的神经系统中的功能目前尚不清楚。在这项研究中，我们证明cd59在发育中的SCs的一个子集中表达。利用cd59突变斑马鱼，我们发现发育中的SCs增殖过度，神经可能减少了髓磷脂体积，改变了髓磷脂超微结构，扰乱了Ranvier组装节点。最后，我们证明了cd59突变体中的补体活性升高，抑制炎症可使SC增殖、髓磷脂体积和Ranvier淋巴结恢复到野生型水平。总之，这项工作确定了Cd59和发育性炎症是髓鞘胶质细胞发育的关键参与者，强调了胶质细胞和先天免疫系统之间的合作，以确保正常的神经发育。脊椎动物的神经系统是由复杂的神经细胞网络组成的，这些神经细胞相互传递信号。除了这些细胞外，还有一些辅助细胞帮助神经发挥作用。例如，雪旺细胞通过将其长长的延伸包裹在一种叫做髓磷脂的脂肪膜中，帮助神经细胞更快地传递信息。当髓磷脂不能正常产生时，就会干扰神经细胞之间的信号，导致神经系统缺陷。雪旺细胞与胚胎中的神经细胞同时成熟。然而，尚不完全清楚雪旺细胞在发育过程中如何产生髓磷脂。为了进行研究，Wiltbank等人研究了斑马鱼的胚胎，与其他脊椎动物不同，斑马鱼的胚胎是透明的，并且在子宫外发育。这些特性使得用显微镜实时观察神经系统细胞的生长变得更加容易。首先，研究小组分析了从斑马鱼和老鼠的胚胎中收集的基因数据，以寻找发育过程中雪旺细胞中高度丰富的基因。这导致了一种名为cd59的基因的发现，该基因编码一种蛋白质，这种蛋白质也与免疫系统相互作用。为了弄清雪旺细胞是否依赖cd59， Wiltbank等人删除了斑马鱼胚胎中的cd59基因。没有cd59，雪旺细胞产生了太多的自身拷贝，这反过来又损害了髓磷脂的适当产生。由于cd59编码的蛋白质通常会平衡炎症水平，因此失去该基因可能会过度激活斑马鱼胚胎中的免疫系统。为了支持这一假设，当cd59突变胚胎用抗炎药物处理时，这纠正了雪旺细胞的过度生产并恢复了髓磷脂的形成。综上所述，这些发现揭示了炎症如何帮助决定发育过程中产生的雪旺细胞数量，而cd59阻止了这一过程的发生。这表明，神经系统和免疫系统可能共同构建神经系统。在未来，研究cd59在人类神经系统发育过程中是否以类似的方式起作用将是有趣的。
Efficient neurotransmission is essential for organism survival and is enhanced by myelination. However, the genes that regulate myelin and myelinating glial cell development have not been fully characterized. Data from our lab and others demonstrates that cd59, which encodes for a small GPI-anchored glycoprotein, is highly expressed in developing zebrafish, rodent, and human oligodendrocytes (OLs) and Schwann cells (SCs), and that patients with CD59 dysfunction develop neurological dysfunction during early childhood. Yet, the function of Cd59 in the developing nervous system is currently undefined. In this study, we demonstrate that cd59 is expressed in a subset of developing SCs. Using cd59 mutant zebrafish, we show that developing SCs proliferate excessively and nerves may have reduced myelin volume, altered myelin ultrastructure, and perturbed node of Ranvier assembly. Finally, we demonstrate that complement activity is elevated in cd59 mutants and that inhibiting inflammation restores SC proliferation, myelin volume, and nodes of Ranvier to wildtype levels. Together, this work identifies Cd59 and developmental inflammation as key players in myelinating glial cell development, highlighting the collaboration between glia and the innate immune system to ensure normal neural development. The nervous system of vertebrates is made of up of complex networks of nerve cells that send signals to one another. In addition to these cells, there are a number of supporting cells that help nerves carry out their role. Schwann cells, for example, help nerve cells to transmit information faster by wrapping their long extensions in a fatty membrane called myelin. When myelin is not produced properly, this can disturb the signals between nerve cells, leading to neurological defects. Schwann cells mature simultaneously with nerve cells in the embryo. However, it was not fully understood how Schwann cells generate myelin during development. To investigate, Wiltbank et al. studied the embryos of zebrafish, which, unlike other vertebrates, are transparent and develop outside of the womb. These qualities make it easier to observe how cells in the nervous system grow in real-time using a microscope. First, the team analyzed genetic data collected from the embryo of zebrafish and mice to search for genes that are highly abundant in Schwann cells during development. This led to the discovery of a gene called cd59, which codes for a protein that also interacts with the immune system. To find out whether Schwann cells rely on cd59, Wiltbank et al. deleted the cd59 gene in zebrafish embryos. Without cd59, the Schwann cells produced too many copies of themselves and this, in turn, impaired the appropriate production of myelin. Since the protein encoded by cd59 normally balances inflammation levels, it was possible that losing this gene overactivated the immune system in the zebrafish embryos. In support of this hypothesis, when the cd59 mutant embryos were treated with an anti-inflammatory drug, this corrected Schwann cell overproduction and restored myelin formation. Taken together, these findings reveal how inflammation helps determine the number of Schwann cells produced during development, and that cd59 prevents this process from getting carried away. This suggests that the nervous system and immune system may work together to build the nervous system. In the future, it will be interesting to investigate whether cd59 acts in a similar way during the development of the human nervous system.
DOI：
10.1002/dvdy.24529
发表时间：
2017-11
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
--
作者：
Morris AD;Erisir A;Criswell SJ;Kucenas S
通讯作者：
Kucenas S
DOI：
10.4049/jimmunol.1203072
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Denny KJ;Coulthard LG;Jeanes A;Lisgo S;Simmons DG;Callaway LK;Wlodarczyk B;Finnell RH;Woodruff TM;Taylor SM
通讯作者：
Taylor SM
DOI：
10.1083/jcb.7.1.107
发表时间：
1960-02
期刊：
The Journal of biophysical and biochemical cytology
影响因子：
--
作者：
MATURANA HR
通讯作者：
MATURANA HR