title: FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons.
abstract: Netrin-1 induces repulsive axon guidance by binding to the mammalian Unc5 receptor family (Unc5A-Unc5D). Mouse genetic analysis of selected members of the Unc5 family, however, revealed essential functions independent of Netrin-1, suggesting the presence of other ligands. Unc5B was recently shown to bind fibronectin and leucine-rich transmembrane protein-3 (FLRT3), although the relevance of this interaction for nervous system development remained unclear. Here, we show that the related Unc5D receptor binds specifically to another FLRT protein, FLRT2. During development, FLRT2/3 ectodomains (ECDs) are shed from neurons and act as repulsive guidance molecules for axons and somata of Unc5-positive neurons. In the developing mammalian neocortex, Unc5D is expressed by neurons in the subventricular zone (SVZ), which display delayed migration to the FLRT2-expressing cortical plate (CP). Deletion of either FLRT2 or Unc5D causes a subset of SVZ-derived neurons to prematurely migrate towards the CP, whereas overexpression of Unc5D has opposite effects. Hence, the shed FLRT2 and FLRT3 ECDs represent a novel family of chemorepellents for Unc5-positive neurons and FLRT2/Unc5D signalling modulates cortical neuron migration.
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Am Klopferspitz, Martinsried, Germany.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Falko
authors.initials: F
authors.lastname: Hampel
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hata
authors.forename: Daniel
authors.initials: D
authors.lastname: Del Toro
authors.forename: Manuela
authors.initials: M
authors.lastname: Schwark
authors.forename: Elena
authors.initials: E
authors.lastname: Kvachnina
authors.forename: Martin
authors.initials: M
authors.lastname: Bastmeyer
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
authors.forename: Victor
authors.initials: V
authors.lastname: Tarabykin
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
authors.forename: Joaquim
authors.initials: J
authors.lastname: Egea
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D019426:Integrases / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C514258:FLRT1 protein, mouse; C514259:FLRT2 protein, mouse; C514260:FLRT3 protein, mouse; D008562:Membrane Glycoproteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617308:Unc5A protein, mouse; D000075388:Netrin-1; C045073:Cre recombinase; D019426:Integrases