Inverse expression of Ten3 and Lphn2 across the developing mouse brain suggests a global strategy for circuit...

Precise wiring of neural circuits requires molecular strategies that ensure accurate target selection across diverse brain regions. Here, we identify inverse expression between a ligand-receptor pair, teneurin-3 (Ten3) and latrophilin-2 (Lphn2), across the developing mouse brain. Ten3 and Lphn2 exhibit inverse expression gradients along a retinotopic axis orthogonal to the ephrinA and EphA gradients, along the tonotopic axis across multiple brainstem auditory nuclei, and along the dorsomedial-ventrolateral axis in striatum and pallidum. Their inverse expression also creates discrete domains of cerebellar Purkinje cells (PCs) and cerebellar nuclei (CN). Using conditional-tag mice, we show that inverse Ten3 and Lphn2 expression patterns predict connectivity, following a "Ten3→Ten3, Lphn2→Lphn2" rule in all above circuits, and that Lphn2 is required in executing this rule in PCs→CN projection. Our findings suggest a global strategy of coordinating gene expression of key wiring molecules with circuit connectivity across the developing brain.