Departments of Neurobiology, Ophthalmology, and Cell Biology, Duke University School of Medicine, Box 3802, Durham, NC 27710, USA.
Helen Wills Neuroscience Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Dev Cell. 2023 Oct 23;58(20):2080-2096.e7. doi: 10.1016/j.devcel.2023.07.011. Epub 2023 Aug 8.
During nervous system development, neurons choose synaptic partners with remarkable specificity; however, the cell-cell recognition mechanisms governing rejection of inappropriate partners remain enigmatic. Here, we show that mouse retinal neurons avoid inappropriate partners by using the FLRT2-uncoordinated-5 (UNC5) receptor-ligand system. Within the inner plexiform layer (IPL), FLRT2 is expressed by direction-selective (DS) circuit neurons, whereas UNC5C/D are expressed by non-DS neurons projecting to adjacent IPL sublayers. In vivo gain- and loss-of-function experiments demonstrate that FLRT2-UNC5 binding eliminates growing DS dendrites that have strayed from the DS circuit IPL sublayers. Abrogation of FLRT2-UNC5 binding allows mistargeted arbors to persist, elaborate, and acquire synapses from inappropriate partners. Conversely, UNC5C misexpression within DS circuit sublayers inhibits dendrite growth and drives arbors into adjacent sublayers. Mechanistically, UNC5s promote dendrite elimination by interfering with FLRT2-mediated adhesion. Based on their broad expression, FLRT-UNC5 recognition is poised to exert widespread effects upon synaptic partner choices across the nervous system.
在神经系统发育过程中，神经元具有显著特异性地选择突触伴侣；然而，调控排斥不合适伴侣的细胞-细胞识别机制仍不清楚。在这里，我们发现小鼠视网膜神经元通过使用 FLRT2-UNC5（未协调 5）受体-配体系统来避免不合适的伴侣。在神经内丛状层（IPL）中，FLRT2 由方向选择性（DS）电路神经元表达，而 UNC5C/D 由投射到相邻 IPL 亚层的非 DS 神经元表达。体内功能获得和功能丧失实验表明，FLRT2-UNC5 结合消除了从 DS 电路 IPL 亚层中偏离的生长中的 DS 树突。FLRT2-UNC5 结合的破坏允许靶向错误的树突分支持续存在、扩展并从不合适的伴侣获得突触。相反，UNC5C 在 DS 电路亚层中的错误表达会抑制树突生长并将树突分支驱动到相邻的亚层。从机制上讲，UNC5 通过干扰 FLRT2 介导的黏附来促进树突消除。基于其广泛的表达，FLRT-UNC5 识别有望对整个神经系统中的突触伴侣选择产生广泛影响。
