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.

Spatiotemporal Molecular Approach of in utero Electroporation to Functionally Decipher Endophenotypes in Neurodevelopmental Disorders.

We have only just begun to decipher the complexity of our brain, including its maturation. Correct brain development and communication among brain areas are crucial for proper cognitive behavior. Brain area-specific genes expressed within a particular time window direct neurodevelopmental events such as proliferation, migration, axon guidance, dendritic arborization, and synaptogenesis. These genes can pose as susceptibility factors in neurodevelopmental disorders eventually resulting in area-specific cognitive deficits. Therefore, in utero electroporation (IUE)-mediated gene transfer can aid in creating valuable animal models in which the regionality and time of expression can be restricted for the targeted gene(s). Moreover, through the use of cell-type-specific molecular constructs, expression can be altered in a particular neuronal subset within a distinct area such that we are now able to causally link the function of that gene in that brain region to the etiology of the disorder. Thus, IUE-mediated gene transfer is an attractive molecular technique to spatiotemporally address the developmental aspects of gene function in relation to neurodevelopmental disorder-associated endophenotypes.