Rejection of inappropriate synaptic partners in mouse retina mediated by transcellular FLRT2-UNC5 signaling

During nervous system development, neurons choose synaptic partners with remarkable specificity; howev-er, 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-uncoordi-nated-5 (UNC5) receptor-ligand system. Within the inner plexiform layer (IPL), FLRT2 is expressed by direc-tion-selective (DS) circuit neurons, whereas UNC5C/D are expressed by non-DS neurons projecting to adja-cent 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 inappro-priate partners. Conversely, UNC5C misexpression within DS circuit sublayers inhibits dendrite growth and drives arbors into adjacent sublayers. Mechanistically, UNC5s promote dendrite elimination by inter-fering 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.

Automated summary

During nervous system development, the FLRT2-UNC5 receptor-ligand system plays a crucial role in helping neurons reject inappropriate synaptic partners and regulate dendrite growth and localization.