title: Subdomain-mediated axon-axon signaling and chemoattraction cooperate to regulate afferent innervation of the lateral habenula.
abstract: 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.
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Ewoud Roberto Eduard
authors.initials: ERE
authors.lastname: Schmidt
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Sara
authors.initials: S
authors.lastname: Brignani
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Youri
authors.initials: Y
authors.lastname: Adolfs
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lemstra
authors.affiliation: Proteomics Centre and Department of Cell Biology, Erasmus University Medical Centre, Dr Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Department of Basic Science, Faculty of Medicine, University of Crete and Institute of Molecular Biology and Biotechnology, Vassilika Vouton, Heraklion GR-7110, Greece.
authors.forename: Marina
authors.initials: M
authors.lastname: Vidaki
authors.affiliation: Queensland Brain Institute and The School of Biomedical Sciences, University of Queensland, Building 79, St Lucia Campus, Brisbane, QLD 4067, Australia.
authors.forename: Amber-Lee Skye
authors.initials: AS
authors.lastname: Donahoo
authors.affiliation: Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411 Tartu, Estonia.
authors.forename: Kersti
authors.initials: K
authors.lastname: Lilleväli
authors.affiliation: Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411 Tartu, Estonia.
authors.forename: Eero
authors.initials: E
authors.lastname: Vasar
authors.affiliation: Queensland Brain Institute and The School of Biomedical Sciences, University of Queensland, Building 79, St Lucia Campus, Brisbane, QLD 4067, Australia.
authors.forename: Linda Jane
authors.initials: LJ
authors.lastname: Richards
authors.affiliation: Department of Basic Science, Faculty of Medicine, University of Crete and Institute of Molecular Biology and Biotechnology, Vassilika Vouton, Heraklion GR-7110, Greece.
authors.forename: Domna
authors.initials: D
authors.lastname: Karagogeos
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Sharon Margriet
authors.initials: SM
authors.lastname: Kolk
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands. Electronic address: r.j.pasterkamp@umcutrecht.nl.
authors.forename: Ronald Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology; D019262:Habenula / Q000502:physiology*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D000075388:Netrin-1; D009434:Neural Pathways / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology*; D013569:Synapses / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002630:Chemotactic Factors; D051907:Lysosomal Membrane Proteins; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1