The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM-EGL-15/FGFR Receptor Complex
The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM-EGL-15/FGFR Receptor Complex
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DOI：
10.1016/j.celrep.2015.04.057
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发表时间：
2015-06-09
期刊：
影响因子：
8.8
通讯作者：
Buelow, Hannes E.
中科院分区：
文献类型：
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作者：
Diaz-Balzac, Carlos A.;Lazaro-Pena, Maria I.;Buelow, Hannes E.
轴突分支对于神经回路的正确组装是必不可少的，但它仍然是一个鲜为人知的过程。例如，神经细胞黏附分子KAL-1/anosmin-1在Kallmann综合征中突变，通过几乎不为人所知的机制来调节轴突分支。在这里，我们证明KAL-1/anosmin-1作为一种自分泌辅助因子与EGL-17/FGF通过一个由保守的细胞黏附分子SAX-7/L1CAM和成纤维细胞生长因子受体EGL-15/FGFR组成的受体复合体来介导轴突分支。这种蛋白质复合体在人类中似乎是保守的，它需要SAX-7/L1CAM的免疫球蛋白(Ig)结构域和KAL-1/anosmin-1的Fn(III)结构域才能在体外形成和在体内发挥作用。EGL-15/FGFR的激酶结构域是分支所必需的，遗传证据表明，ras介导的信号转导在EGL-15/FGFR下游是必要的。我们的研究建立了一条在神经系统发育过程中调节轴突分支的分子途径。
Neurite branching is essential for correct assembly of neural circuits, yet it remains a poorly understood process. For example, the neural cell adhesion molecule KAL-1/anosmin-1, which is mutated in Kallmann syndrome, regulates neurite branching through mechanisms largely unknown. Here, we show that KAL-1/anosmin-1 mediates neurite branching as an autocrine co-factor with EGL-17/FGF through a receptor complex consisting of the conserved cell adhesion molecule SAX-7/L1CAM and the fibroblast growth factor receptor EGL-15/FGFR. This protein complex, which appears conserved in humans, requires the immunoglobulin (Ig) domains of SAX-7/L1CAM and the FN(III) domains of KAL-1/anosmin-1 for formation in vitro as well as function in vivo. The kinase domain of the EGL-15/FGFR is required for branching, and genetic evidence suggests that ras-mediated signaling downstream of EGL-15/FGFR is necessary to effect branching. Our studies establish a molecular pathway that regulates neurite branching during development of the nervous system.