Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Sci Rep. 2018 May 8;8(1):7292. doi: 10.1038/s41598-018-24064-0.
Linx is a member of the leucine-rich repeat and immunoglobulin family of membrane proteins which has critical roles in the development of the peripheral nervous system and forebrain connectivity. A previous study showed that Linx is expressed in projection neurons in the cortex and in cells that comprise the passage to the prethalamus that form the internal capsule, indicating the involvement of Linx in axon guidance and cell-cell communication. In this study, we found that Linx-deficient mice develop severe hydrocephalus and die perinatally by unknown mechanisms. Importantly, mice heterozygous for the linx gene exhibited defects in the development of the anterior commissure in addition to hydrocephalus, indicating haploinsufficiency of the linx gene in forebrain development. In N1E-115 neuroblastoma cells and primary cultured hippocampal neurons, Linx depletion led to impaired neurite extension and an increase in cell body size. Consistent with this, but of unknown significance, we found that Linx interacts with and upregulates the activity of Rho-kinase, a modulator of many cellular processes including cytoskeletal organization. These data suggest a role for Linx in the regulation of complex forebrain connectivity, and future identification of its extracellular ligand(s) will help clarify this function.
Linx 是富含亮氨酸重复和免疫球蛋白家族的膜蛋白成员，在周围神经系统和前脑连接的发育中起着关键作用。先前的研究表明，Linx 在皮质中的投射神经元和构成内囊的前丘脑传入细胞中表达，表明 Linx 参与了轴突导向和细胞间通讯。在这项研究中，我们发现 Linx 缺失的小鼠会发生严重的脑积水，并通过未知机制在围产期死亡。重要的是，Linx 基因杂合子的小鼠除了脑积水外，还表现出前连合发育缺陷，表明 Linx 基因在前脑发育中存在单倍不足。在 N1E-115 神经母细胞瘤细胞和原代培养的海马神经元中，Linx 缺失导致轴突延伸受损和细胞体增大。与此一致，但意义不明，我们发现 Linx 与 Rho-激酶相互作用并上调其活性，Rho-激酶是许多细胞过程（包括细胞骨架组织）的调节剂。这些数据表明 Linx 在调节复杂的前脑连接中起作用，未来鉴定其细胞外配体将有助于阐明其功能。
