Oligodendrocyte-derived laminin-γ1 regulates the blood-brain barrier and CNS myelination in mice

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-04-16 DOI:10.1016/j.celrep.2024.114123

Minkyung Kang, Yao Yao

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Abstract

Although oligodendrocytes (OLs) synthesize laminin-γ1, the most widely used γ subunit, its functional significance in the CNS remains unknown. To answer this important question, we generated a conditional knockout mouse line with laminin-γ1 deficiency in OL lineage cells (γ1-OKO). γ1-OKO mice exhibit weakness/paralysis and die by post-natal day 33. Additionally, they develop blood-brain barrier (BBB) disruption in the cortex and striatum. Subsequent studies reveal decreased major facilitator superfamily domain containing 2a expression and increased endothelial caveolae vesicles, but unaltered tight junction protein expression and tight junction ultrastructure, indicating a transcellular, rather than a paracellular, mechanism of BBB breakdown. Furthermore, significantly reduced OL lineage cells, OL precursor cells (OPCs), proliferating OPCs, and mature OLs are observed in γ1-OKO brains in a region-specific manner. Consistent with this finding, various defects in myelination are detected in γ1-OKO brains at biochemical and ultrastructural levels. Overall, these results highlight important roles of OL-derived laminin-γ1 in BBB maintenance and OL biology (proliferation, differentiation, and myelination).

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源于少突胶质细胞的层粘连蛋白-γ1调节小鼠的血脑屏障和中枢神经系统髓鞘化

尽管少突胶质细胞（OLs）能合成层粘连蛋白-γ1（最广泛使用的γ亚基），但它在中枢神经系统中的功能意义仍然未知。为了回答这一重要问题，我们在 OL 系细胞中产生了缺乏层粘连蛋白-γ1 的条件性基因敲除小鼠品系（γ1-OPO）。γ1-OKO小鼠表现出虚弱/瘫痪，并在出生后第33天死亡。此外，它们的大脑皮层和纹状体会出现血脑屏障（BBB）破坏。随后的研究发现，含 2a 的主要促进因子超家族结构域表达减少，内皮洞穴小泡增加，但紧密连接蛋白表达和紧密连接超微结构没有改变，这表明 BBB 破坏的机制是跨细胞的，而不是旁细胞的。此外，在 γ1-OKO 大脑中观察到的 OL 系细胞、OL 前体细胞（OPCs）、增殖的 OPCs 和成熟的 OLs 以区域特异性的方式明显减少。与这一发现相一致的是，γ1-OKO 大脑在生化和超微结构水平上存在各种髓鞘化缺陷。总之，这些结果突显了源于OL的层粘连蛋白-γ1在BBB维持和OL生物学（增殖、分化和髓鞘化）中的重要作用。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.