During nervous system development, navigating axons ‘decide’ whether or not to cross the midline. Various factors that influence axon guidance and midline crossing have been identified but it remains unclear if any one transcription factor can drive the complete midline crossing transcriptional programme. Here (), Yasuyuki Inamata and Ryuichi Shirasaki report that a single homeodomain transcription factor, Dbx1, assigns midline-crossing identity at the progenitor stage in mice. The researchers show that Dbx1 is expressed in a subset of neural progenitors in the dorsal midbrain. Lineage tracing demonstrates that midbrain commissural neurons, which cross the midline, are generated selectively from Dbx1-positive progenitors. Furthermore, gain- and loss-of-function experiments show that Dbx1 is necessary and sufficient for midline crossing. Finally, the authors show that Dbx1 controls a molecular programme that controls the expression of Robo3, an essential regulator of midline crossing, on commissural neurons while repressing the ipsilateral neuron genetic programme. These findings reveal an unanticipated regulatory layer within the transcriptional cascade that controls nervous system wiring.
