title: Evidence for topographic guidance of dopaminergic axons by differential Netrin-1 expression in the striatum.
abstract: There are two main subgroups of midbrain dopaminergic (DA) neurons: the more medially located ventral tegmental area (VTA) DA neurons, which have axons that innervate the ventral-lateral (VL) striatum, and the more laterally located substantia nigra (SN) DA neurons, which preferentially degenerate in Parkinson's disease (PD) and have axons that project to the dorsal-medial (DM) striatum. DA axonal projections in the striatum are not discretely localized and they arborize widely, however they do not stray from one zone to the other so that VTA axons remain in the VL zone and SN axons in the DM zone. Here we provide evidence that Netrin-1 acts in a novel fashion to topographically pattern midbrain DA axons into these two striatal zones by means of a gradient of Netrin-1 in the striatum and by differential attraction of the axons to Netrin-1. Midbrain DA neurons are attracted to the striatum in culture and this attraction is blocked by an anti-DCC (Netrin receptor) antibody. Mechanistically, outgrowth of both VTA and SN DA axons is stimulated by Netrin-1, but the two populations of DA axons respond optimally to overlapping but distinct concentrations of Netrin-1, with SN axons preferring lower concentrations and VTA axons preferring higher concentrations. In vivo this differential preference is closely mirrored by differences in Netrin-1 expression in their respective striatal target fields. In vivo in mice lacking Netrin-1, DA axons that reach the striatum fail to segregate into two terminal zones and to fully innervate the striatum. Our results reveal novel actions for Netrin-1 and provide evidence for a mechanism through which DA axons can selectively innervate one of two terminal zones in the striatum but have free reign to arborize widely within a terminal zone.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: The Rockefeller University, New York, NY, United States.
authors.forename: Terence
authors.initials: T
authors.lastname: Duarte
authors.affiliation: The Rockefeller University, New York, NY, United States.
authors.forename: Arif
authors.initials: A
authors.lastname: Kocabas
authors.affiliation: Department of Biology, Stanford University, Stanford, CA, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Works
authors.affiliation: Department of Biology, Stanford University, Stanford, CA, United States.
authors.forename: Susan K
authors.initials: SK
authors.lastname: McConnell
authors.affiliation: Department of Biology, Stanford University, Stanford, CA, United States; The Rockefeller University, New York, NY, United States. Electronic address: mhynes@rockefeller.edu.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Hynes
mesh_terms: D000367:Age Factors; D000818:Animals; D001369:Axons / Q000502:physiology*; D019556:COS Cells; D002645:Chickens; D002522:Chlorocebus aethiops; D003342:Corpus Striatum / Q000166:cytology*; D000075389:DCC Receptor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C511143:Bcl11b protein, mouse; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D014446:Tyrosine 3-Monooxygenase
keywords: Axon guidance; Dopaminergic neuron; Gradient; Netrin; Striatum; Substantia nigra