title: EphrinA5 Signaling Is Required for the Distinctive Targeting of Raphe Serotonin Neurons in the Forebrain.
abstract: Serotonin (5-HT) neurotransmission in the brain relies on a widespread axon terminal network originating from the hindbrain raphe nuclei. These projections are topographically organized such that the dorsal (DR), and median raphe (MnR) nuclei have different brain targets. However, the guidance molecules involved in this selective targeting in development are unknown. Here, we show the implication of ephrinA5 signaling in this process. We find that theEphA5gene is selectively expressed in a subset of 5-HT neurons during embryonic and postnatal development. Highest coexpression ofEphA5and the 5-HT marker Tph2 is found in the DR, with lower coexpression in the MnR, and hardly any colocalization of the caudal raphe in the medulla. Accordingly, ephrinA induced a dose-dependent collapse response of 5-HT growth cones cultured from rostral but not caudal raphe. Ectopic expression of ephrinA3, afterin uteroelectroporation in the amygdala and piriform cortex, repelled 5-HT raphe fiber ingrowth. Conversely, misplaced DR 5-HT axons were found in ephrin A5 knockout mice in brain regions that are normally only targeted by MnR 5-HT axons. This causes an overall increase in the density of 5-HT innervation in the ventromedial hypothalamus, the suprachiasmatic nucleus, and the olfactory bulb. All these brain areas have high expression of ephrinAs at the time of 5-HT fiber ingrowth. Present results show for the first time the role of a guidance molecule for the region-specific targeting of raphe neurons. This has important implications to understand how functional parsing of central 5-HT neurons is established during development.
authors.affiliation: Inserm UMR-S 839, 75005, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut du Fer à Moulin, Paris, France.
authors.forename: Teng
authors.identifier: 0000-0003-3701-0002
authors.initials: T
authors.lastname: Teng
authors.affiliation: Inserm 1084, Poitiers, France; Université de Poitiers, Poitiers, France.
authors.forename: Afsaneh
authors.identifier: 0000-0002-9375-6506
authors.initials: A
authors.lastname: Gaillard
authors.affiliation: Inserm UMR-S 839, 75005, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut du Fer à Moulin, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Muzerelle
authors.affiliation: Inserm UMR-S 839, 75005, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut du Fer à Moulin, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gaspar
mesh_terms: D000367:Age Factors; D000679:Amygdala / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D036386:Ephrin-A5 / Q000235:genetics / Q000378:metabolism*; D036342:Ephrins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D066267:Midbrain Raphe Nuclei / Q000166:cytology*; D009434:Neural Pathways / Q000502:physiology; D016548:Prosencephalon / Q000166:cytology* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D036386:Ephrin-A5; D036342:Ephrins; C484684:Fev protein, mouse; D050486:Serotonin Plasma Membrane Transport Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: Ephrin; amygdala; culture; hypothalamus; in utero electroporation; olfactory bulb