Nephronectin-integrin α8 signaling is required for proper migration of periocular neural crest cells during chick corneal development.
Nephronectin-integrin α8 signaling is required for proper migration of periocular neural crest cells during chick corneal development.
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DOI：
10.7554/elife.74307
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发表时间：
2022-03-03
期刊：
影响因子：
7.7
通讯作者：
Lwigale P
中科院分区：
文献类型：
--
作者：
Ma J;Bi L;Spurlin J;Lwigale P
在发育过程中，细胞在组织边界聚集，形成器官的正常组织结构。然而，细胞如何分离成组织前体在很大程度上仍然未知。角膜发育是这一过程的一个很好的例子，其中神经嵴细胞在迁移和分化成角膜细胞之前聚集在眼周区域。我们最近的RNA-seq分析确定了在角膜发育的早期阶段肾连蛋白（Npnt）转录本的上调，其中其功能尚未研究。我们发现Npnt mRNA和蛋白质在各种眼组织中表达，包括迁移性眼周神经嵴（pNC），其也表达整合素α 8（Itgα8）受体。敲低Npnt或Itgα8均减弱角膜发育，而过表达Npnt则导致角膜增厚。此外，缺乏RGD结合位点的Npnt变体的过表达不影响角膜厚度。Npnt的敲低和增强均未引起细胞增殖的显著变化，表明Npnt指导pNC迁移到角膜中。体外分析表明，Npnt促进pNC从受损的眼周间充质迁移，这需要Itgα8、粘着斑激酶和Rho激酶。总之，这些数据表明，Npnt通过作为Itgα8阳性pNC细胞的底物发挥作用，增强细胞迁移到假定的角膜细胞外基质中。
During development, cells aggregate at tissue boundaries to form normal tissue architecture of organs. However, how cells are segregated into tissue precursors remains largely unknown. Cornea development is a perfect example of this process whereby neural crest cells aggregate in the periocular region prior to their migration and differentiation into corneal cells. Our recent RNA-seq analysis identified upregulation of nephronectin (Npnt) transcripts during early stages of corneal development where its function has not been investigated. We found that Npnt mRNA and protein are expressed by various ocular tissues, including the migratory periocular neural crest (pNC), which also express the integrin alpha 8 (Itgα8) receptor. Knockdown of either Npnt or Itgα8 attenuated cornea development, whereas overexpression of Npnt resulted in cornea thickening. Moreover, overexpression of Npnt variants lacking RGD-binding sites did not affect corneal thickness. Neither the knockdown nor augmentation of Npnt caused significant changes in cell proliferation, suggesting that Npnt directs pNC migration into the cornea. In vitro analyses showed that Npnt promotes pNC migration from explanted periocular mesenchyme, which requires Itgα8, focal adhesion kinase, and Rho kinase. Combined, these data suggest that Npnt augments cell migration into the presumptive cornea extracellular matrix by functioning as a substrate for Itgα8-positive pNC cells.