Cx43-Dependent Skeletal Phenotypes Are Mediated by Interactions between the Hapln1a-ECM and Sema3d during Fin Regeneration.
Cx43-Dependent Skeletal Phenotypes Are Mediated by Interactions between the Hapln1a-ECM and Sema3d during Fin Regeneration.
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DOI：
10.1371/journal.pone.0148202
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Iovine MK
中科院分区：
文献类型：
--
作者：
Govindan J;Tun KM;Iovine MK
骨骼发育是一个严格调控的过程，需要细胞之间进行适当的沟通，以有效地交换信息。对鳍长突变体的分析表明，在斑马鱼尾鳍再生过程中，差距连接蛋白连接蛋白43（Cx43）协调细胞增殖（生长）和关节形成（图案化）。以前的研究表明，细胞外基质（ECM）蛋白Hyaluronan和蛋白聚糖连接蛋白1a（Hapln 1a）的分子和功能下游的Cx43，和Hapln 1a敲低导致减少糖胺聚糖乙酰透明质酸。在这里，我们发现蛋白聚糖聚集蛋白聚糖在Hapln 1a敲低后类似地减少。值得注意的是，我们证明了透明质酸和聚集蛋白聚糖都是生长和图案化所必需的。此外，我们提供的证据表明，Hapln 1a-ECM稳定分泌的生长因子Semaphorin 3d（Sema 3d），这已被独立地证明介导Cx43依赖表型再生过程中。hapln 1a和sema 3d的双敲低揭示了协同作用。此外，haplnla敲低表型被Sema 3d过表达拯救。因此，Hapln 1a维持ECM的特定组分的组成，这似乎是稳定至少一种生长因子Sema 3d所需的。我们认为Hapln 1a依赖性ECM为Sema 3d的稳定和功能提供了所需的条件。ECM和信号分子之间的相互作用是复杂的，我们的研究证明了Sema 3d信号转导对Hapln 1a-ECM组分的需求。
Skeletal development is a tightly regulated process and requires proper communication between the cells for efficient exchange of information. Analysis of fin length mutants has revealed that the gap junction protein Connexin43 (Cx43) coordinates cell proliferation (growth) and joint formation (patterning) during zebrafish caudal fin regeneration. Previous studies have shown that the extra cellular matrix (ECM) protein Hyaluronan and Proteoglycan Link Protein1a (Hapln1a) is molecularly and functionally downstream of Cx43, and that hapln1a knockdown leads to reduction of the glycosaminoglycan hyaluronan. Here we find that the proteoglycan aggrecan is similarly reduced following Hapln1a knockdown. Notably, we demonstrate that both hyaluronan and aggrecan are required for growth and patterning. Moreover, we provide evidence that the Hapln1a-ECM stabilizes the secreted growth factor Semaphorin3d (Sema3d), which has been independently shown to mediate Cx43 dependent phenotypes during regeneration. Double knockdown of hapln1a and sema3d reveal synergistic interactions. Further, hapln1a knockdown phenotypes were rescued by Sema3d overexpression. Therefore, Hapln1a maintains the composition of specific components of the ECM, which appears to be required for the stabilization of at least one growth factor, Sema3d. We propose that the Hapln1a dependent ECM provides the required conditions for Sema3d stabilization and function. Interactions between the ECM and signaling molecules are complex and our study demonstrates the requirement for components of the Hapln1a-ECM for Sema3d signal transduction.