Subdomain-mediated axon-axon signaling and chemoattraction cooperate to regulate afferent innervation of the lateral habenula

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

Subdomain--Mediated Axon--Axon Signalingand Chemoattraction Cooperate to RegulateAfferent Innervation of the Lateral Habenula

SUMMARY 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)nucleusspecific connections are established and whether axonderived 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. INTRODUCTION The formation of precise connections between afferent axons and their partner neurons is essential for the assembly of functional neural circuits. The organization of the nervous system in two main anatomical units, i.e., brain nuclei and laminated structures, facilitates this process by spatially grouping synaptic partners and enabling subdomain-restricted expression of instructive cues. Despite the important role of these organizing principles, our understanding of the cellular and molecular basis of laminaor subnucleus-specific circuit development is still limited. Our current knowledge of subdomain-specific axon targeting mainly derives from work on laminated structures, and recent studies have uncovered different molecular strategies that control lamina-specific targeting independent of neural activity. This work shows that initially target-derived, membrane-associated, or secreted guidance cues function to direct axon projections to or exclude them from specific layers. Subsequently, combinatorial expression of cell adhesion molecules facilitates the formation of contacts between matched pre-and postsynaptic neuron