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

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), throughout the developing mouse brain. Ten3 and Lphn2 exhibit inverse expression gradients along a retinotopic axis orthogonal to the ephrin-A 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 and cerebellar nuclei along the mediolateral axis. 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. We further demonstrate a functional role for Lphn2 in executing this rule in Purkinje cells → cerebellar nuclei projection. Our findings reveal a global strategy of coordinating gene expression of key wiring molecules with circuit connectivity across the developing brain.