A dominant feature of neural circuitry is the organization of neuronal projections and synapses into specific brain nuclei or laminae. Lamina-specific connectivity is controlled by the selective expression of extracellular guidance and adhesion molecules in the target field. However, how (sub)nucleus-specific connections are established and whether axon-derived cues contribute to subdomain targeting are largely unknown. Here, we demonstrate that the lateral subnucleus of the habenula (lHb) determines its own afferent innervation by sending out efferent projections that express the cell adhesion molecule LAMP to reciprocally collect and guide dopaminergic afferents to the lHb-a phenomenon we term subdomain-mediated axon-axon signaling. This process of reciprocal axon-axon interactions cooperates with lHb-specific chemoattraction mediated by Netrin-1, which controls axon target entry, to ensure specific innervation of the lHb. We propose that cooperation between pretarget reciprocal axon-axon signaling and subdomain-restricted instructive cues provides a highly precise and general mechanism to establish subdomain-specific neural circuitry.

dx.doi.org/10.1016/j.neuron.2014.05.036, hdl.handle.net/1765/59182
This work was funded by the European Commission 7th Framework Programme; grant id fp7/222999 - Molecular coding and subset specification of dopamine neurons generating the the meso-limbic and nigro-striatal system. (MDDANEURODEV), This work was funded by the European Commission 7th Framework Programme; grant id fp7/289581 - NPlast - A neuroscience school that aims to preserve and restore neuroplasticity in brain disorders (NPLAST)
Department of Biochemistry

Schmidt, E.R.E, Brignani, S, Adolfs, Y, Lemstra, S, Demmers, J.A.A, Vidaki, M, … Pasterkamp, R.J. (2014). Subdomain-mediated axon-axon signaling and chemoattraction cooperate to regulate afferent innervation of the lateral habenula. Neuron, 83(2), 372–387. doi:10.1016/j.neuron.2014.05.036