The cell surface hyaluronidase TMEM2 plays an essential role in mouse neural crest cell development and survival.
The cell surface hyaluronidase TMEM2 plays an essential role in mouse neural crest cell development and survival.
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细胞表面透明质酸酶TMEM2在小鼠神经脊细胞的发育和存活中起着至关重要的作用。
DOI：
10.1371/journal.pgen.1009765
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发表时间：
2022-07
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
透明质酸（HA）是一种主要的细胞外基质成分，其组织水平在胚胎发育过程中受到动态调节。虽然HA的合成已被证明对胚胎形态发生产生重大影响，但HA周转的分解代谢方面的功能重要性知之甚少。在这里，我们证明了跨膜透明质酸酶TMEM 2在神经嵴发育和神经嵴衍生物的形态发生中起着至关重要的作用，这一点可以通过Wnt 1-Cre介导的Tmem 2基因敲除（Tmem 2CKO）小鼠中存在严重的颅面异常来证明。神经嵴细胞（NCC）是一种迁移性细胞群，可产生不同的细胞谱系，包括颅面复合体，外周神经系统和心脏的一部分。对NCC形成和迁移过程中Tmem 2表达的分析表明，Tmem 2在NCC分层的位点和迁移的Sox 9阳性NCC中表达。在Tmem 2CKO胚胎中，从神经管迁移的NCC数量大大减少。此外，linage跟踪显示，穿越腹侧迁移途径的NCC的数量和迁移后的神经嵴衍生物的数量都显着减少在Tmem 2CKO背景。使用Tmem 2耗尽的小鼠O 9 -1神经嵴细胞的体外研究表明，Tmem 2表达对于这些细胞在含HA的基质上形成粘着斑和迁移到含HA的基质中的能力是必需的。此外，我们发现Tmem 2缺陷型NCC在NCC衍生的组织中表现出增加的凋亡性细胞死亡，这一观察结果通过使用O 9 -1细胞的体外实验得到证实。总的来说，我们的数据表明，TMEM 2介导的HA降解在正常神经嵴发育中起着至关重要的作用。这项研究揭示了迄今尚未认识到的HA降解在胚胎发育中的功能重要性，并强调了Tmem 2在发育过程中的关键作用。作为细胞外基质的主要成分，透明质酸在胚胎组织的细胞外基质中特别丰富，其表达在组织形态发生过程中受到动态调节。透明质酸的组织水平不仅受其合成的调节，还受其降解的调节。然而，奇怪的是，缺乏已知透明质酸酶分子（包括HYAL 1和HYAL 2）的小鼠表现出最小的胚胎表型。因此，我们对胚胎发育中透明质酸代谢的分解代谢方面的作用的理解是相当有限的。在这里，我们表明，TMEM 2，最近确定的透明质酸酶，降解透明质酸的细胞表面，在神经嵴细胞及其衍生物的发展中起着至关重要的作用。我们对Tmem 2条件性敲除小鼠、Tmem 2敲入报告基因小鼠和体外细胞培养物的分析表明，TMEM 2对于产生神经嵴细胞从神经管有效迁移所需的组织环境至关重要。我们的论文首次揭示了透明质酸的降解在胚胎形态发生中起着特定的调节作用，并且透明质酸降解的失调导致严重的发育缺陷。
Hyaluronan (HA) is a major extracellular matrix component whose tissue levels are dynamically regulated during embryonic development. Although the synthesis of HA has been shown to exert a substantial influence on embryonic morphogenesis, the functional importance of the catabolic aspect of HA turnover is poorly understood. Here, we demonstrate that the transmembrane hyaluronidase TMEM2 plays an essential role in neural crest development and the morphogenesis of neural crest derivatives, as evidenced by the presence of severe craniofacial abnormalities in Wnt1-Cre–mediated Tmem2 knockout (Tmem2CKO) mice. Neural crest cells (NCCs) are a migratory population of cells that gives rise to diverse cell lineages, including the craniofacial complex, the peripheral nervous system, and part of the heart. Analysis of Tmem2 expression during NCC formation and migration reveals that Tmem2 is expressed at the site of NCC delamination and in emigrating Sox9-positive NCCs. In Tmem2CKO embryos, the number of NCCs emigrating from the neural tube is greatly reduced. Furthermore, linage tracing reveals that the number of NCCs traversing the ventral migration pathway and the number of post-migratory neural crest derivatives are both significantly reduced in a Tmem2CKO background. In vitro studies using Tmem2-depleted mouse O9-1 neural crest cells demonstrate that Tmem2 expression is essential for the ability of these cells to form focal adhesions on and to migrate into HA-containing substrates. Additionally, we show that Tmem2-deficient NCCs exhibit increased apoptotic cell death in NCC-derived tissues, an observation that is corroborated by in vitro experiments using O9-1 cells. Collectively, our data demonstrate that TMEM2-mediated HA degradation plays an essential role in normal neural crest development. This study reveals the hitherto unrecognized functional importance of HA degradation in embryonic development and highlights the pivotal role of Tmem2 in the developmental process. As a major component of the extracellular matrix, hyaluronan is particularly abundant in the extracellular matrix of embryonic tissues, where its expression is dynamically regulated during tissue morphogenetic processes. Tissue levels of hyaluronan are regulated not only by its synthesis but also by its degradation. Curiously, however, mice lacking known hyaluronidase molecules, including HYAL1 and HYAL2, exhibit minimal embryonic phenotypes. As a result, our understanding of the role of the catabolic aspect of hyaluronan metabolism in embryonic development is quite limited. Here, we show that TMEM2, a recently identified hyaluronidase that degrades hyaluronan on the cell surface, plays a critical role in the development of neural crest cells and their derivatives. Our analyses of Tmem2 conditional knockout mice, Tmem2 knock-in reporter mice, and in vitro cell cultures demonstrate that TMEM2 is essential for generating a tissue environment needed for efficient migration of neural crest cells from the neural tube. Our paper reveals for the first time that the degradation of hyaluronan plays a specific regulatory role in embryonic morphogenesis, and that dysregulation of hyaluronan degradation leads to severe developmental defects.
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影响因子：
64.5
作者：
Freeman SA;Vega A;Riedl M;Collins RF;Ostrowski PP;Woods EC;Bertozzi CR;Tammi MI;Lidke DS;Johnson P;Mayor S;Jaqaman K;Grinstein S
通讯作者：
Grinstein S
DOI：
10.1002/dvg.23105
发表时间：
2018-06
期刊：
Genesis (New York, N.Y. : 2000)
影响因子：
--
作者：
Debbache J;Parfejevs V;Sommer L
通讯作者：
Sommer L
影响因子：
11.8
作者：
De Angelis, Jessica E.;Lagendijk, Anne K.;Smith, Kelly A.
通讯作者：
Smith, Kelly A.
影响因子：
64.8
作者：
Barriga EH;Franze K;Charras G;Mayor R
通讯作者：
Mayor R
影响因子：
4.8
作者：
Chowdhury, Biswajit;Hemming, Richard;Triggs-Raine, Barbara
通讯作者：
Triggs-Raine, Barbara