Semaphorin3d mediates Cx43-dependent phenotypes during fin regeneration.
Semaphorin3d mediates Cx43-dependent phenotypes during fin regeneration.
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DOI：
10.1016/j.ydbio.2012.03.020
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发表时间：
2012-06-15
影响因子：
2.7
通讯作者：
Kathryn Iovine M
中科院分区：
文献类型：
--
作者：
Ton QV;Kathryn Iovine M
缝隙连接是驻留在质膜上的蛋白质通道，允许相邻细胞之间的离子、代谢产物和第二信使的交换。缝隙连接蛋白是缝隙连接通道的亚基。斑马鱼Cx43的突变导致短鳍(Sof B123)表型，这种表型的特征是由于骨鳍射线长度的缺陷而导致短鳍。我们实验室以前的发现表明，在鳍再生过程中，Cx43对细胞增殖和关节形成都是必需的。在这里，我们证明了信号素3d(Sema3d)在Cx43下游的功能。Semas是一种分泌的信号分子，参与多种细胞功能，如轴突引导、细胞迁移、细胞增殖和基因表达。我们认为Sema3d介导了Cx43依赖的细胞增殖和关节形成功能。通过原位杂交和定量RT-PCR，我们证实了Sema3d的表达依赖于Cx43的活性。接下来，我们发现Sema3d的敲除概括了所有sof b123和Cx43的敲除表型，为Sema3d在Cx43下游发挥作用提供了功能证据。为了确定潜在的Sema3d受体(S)，我们研究了神经毛蛋白和丛蛋白的基因表达。其中，nrp2a、plxNA1和plxNA3在再生鳍中表达。吗啉介导的PLXNA1基因敲除并不导致Cx43特异性缺陷，表明PlexinA1在这一途径中不起作用。相反，吗啉介导的nrp2a基因敲除导致FIN过度生长和细胞增殖，但不影响关节的形成。此外，吗啡介导的plxna3基因敲除导致了较短的片段，影响了关节的形成，但没有改变细胞的增殖。综上所述，我们的发现表明Sema3d与Cx43在一个共同的分子途径中发挥作用。此外，对可能的Sema3d受体的功能评估表明，依赖于Cx43的细胞增殖和关节形成利用独立的膜结合受体来调节下游的细胞表型。
Gap junctions are proteinaceous channels that reside at the plasma membrane and permit the exchange of ions, metabolites, and second messengers between neighboring cells. Connexin proteins are the subunits of gap junction channels. Mutations in zebrafish cx43 cause the short fin (sof b123) phenotype which is characterized by short fins due to defects in length of the bony fin rays. Previous findings from our lab demonstrate that Cx43 is required for both cell proliferation and joint formation during fin regeneration. Here we demonstrate that semaphorin3d (sema3d) functions downstream of Cx43. Semas are secreted signaling molecules that have been implicated in diverse cellular functions such as axon guidance, cell migration, cell proliferation, and gene expression. We suggest that Sema3d mediates the Cx43-dependent functions on cell proliferation and joint formation. Using both in situ hybridization and quantitative RT-PCR, we validated that sema3d expression depends on Cx43 activity. Next, we found that knockdown of Sema3d recapitulates all of the sof b123 and cx43-knockdown phenotypes, providing functional evidence that Sema3d acts downstream of Cx43. To identify the potential Sema3d receptor(s), we evaluated gene expression of neuropilins and plexins. Of these, nrp2a, plxna1, and plxna3 are expressed in the regenerating fin. Morpholino-mediated knockdown of plxna1 did not cause cx43-specific defects, suggesting that PlexinA1 does not function in this pathway. In contrast, morpholino-mediated knockdown of nrp2a caused fin overgrowth and increased cell proliferation, but did not influence joint formation. Moreover, morpholino-mediated knockdown of plxna3 caused short segments, influencing joint formation, but did not alter cell proliferation. Together, our findings reveal that Sema3d functions in a common molecular pathway with Cx43. Furthermore, functional evaluation of putative Sema3d receptors suggests that Cx43-dependent cell proliferation and joint formation utilize independent membrane-bound receptors to mediate downstream cellular phenotypes.
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DOI：
10.1073/pnas.122571799
发表时间：
2002-06-25
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
2.7
作者：
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通讯作者：
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