Developmental control of long-range neuronal connections in the mammalian midbrain remains unclear. We explored the mechanisms regulating target selection of the developing superior colliculus (SC). The SC is a midbrain center that directs orienting behaviors and defense responses. We discovered that a transcription factor, Rorβ, controls establishment of axonal projections from the SC to two thalamic nuclei: the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior nucleus (LP). A genetic strategy used to visualize SC circuits revealed that in control animals Rorβ+ neurons abundantly innervate the dLGN but barely innervate the LP. The opposite phenotype was observed in global and conditional Rorb mutants: projections to the dLGN were strongly decreased, and projections to the LP were increased. Furthermore, overexpression of Rorb in the wild type showed increased projections to the dLGN and decreased projections to the LP. In summary, we identified Rorβ as a key developmental mediator of colliculo-thalamic innervation. Such regulation could represent a general mechanism orchestrating long-range neuronal connections in the mammalian brain.
