title: Survival of a Novel Subset of Midbrain Dopaminergic Neurons Projecting to the Lateral Septum Is Dependent on NeuroD Proteins.
abstract: Midbrain dopaminergic neurons are highly heterogeneous. They differ in their connectivity and firing patterns and, therefore, in their functional properties. The molecular underpinnings of this heterogeneity are largely unknown, and there is a paucity of markers that distinguish these functional subsets. In this paper, we report the identification and characterization of a novel subset of midbrain dopaminergic neurons located in the ventral tegmental area that expresses the basic helix-loop-helix transcription factor, Neurogenic Differentiation Factor-6 (NEUROD6). Retrograde fluorogold tracing experiments demonstrate thatNeurod6+midbrain dopaminergic neurons neurons project to two distinct septal regions: the dorsal and intermediate region of the lateral septum. Loss-of-function studies in mice demonstrate thatNeurod6and the closely related family memberNeurod1are both specifically required for the survival of this lateral-septum projecting neuronal subset during development. Our findings underscore the complex organization of midbrain dopaminergic neurons and provide an entry point for future studies of the functions of theNeurod6+subset of midbrain dopaminergic neurons.SIGNIFICANCE STATEMENTMidbrain dopaminergic neurons regulate diverse brain functions, including voluntary movement and cognitive and emotive behaviors. These neurons are heterogeneous, and distinct subsets are thought to regulate different behaviors. However, we currently lack the means to identify and modify gene function in specific subsets of midbrain dopaminergic neurons. In this study, we identify the transcription factor NEUROD6 as a specific marker for a novel subset of midbrain dopaminergic neurons in the ventral midbrain that project to the lateral septum, and we reveal essential roles forNeurod1andNeurod6in the survival of these neurons during development. Our findings highlight the molecular and anatomical heterogeneity of midbrain dopaminergic neurons and contribute to a better understanding of this functionally complex group of neurons.
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, Mill Hill, NW7 1AA, United Kingdom.
authors.forename: Shabana
authors.identifier: 0000-0002-4596-6007
authors.initials: S
authors.lastname: Khan
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, Mill Hill, NW7 1AA, United Kingdom.
authors.forename: Simon R W
authors.identifier: 0000-0002-5741-4664
authors.initials: SR
authors.lastname: Stott
authors.affiliation: Department of Psychiatry and Neurosciences, Université Laval, Quebec G1V 0A6, Canada.|Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec G1J 2G3, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Chabrat
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, Mill Hill, NW7 1AA, United Kingdom.
authors.forename: Anna M
authors.identifier: 0000-0002-4405-783X
authors.initials: AM
authors.lastname: Truckenbrodt
authors.affiliation: Francis Crick Institute, Lincoln's Inn Fields Laboratory, London, WC2A 3LY, United Kingdom, and.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Klaus-Armin
authors.identifier: 0000-0001-8724-9666
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, Mill Hill, NW7 1AA, United Kingdom.
authors.forename: François
authors.identifier: 0000-0003-0432-5067
authors.initials: F
authors.lastname: Guillemot
authors.affiliation: Department of Psychiatry and Neurosciences, Université Laval, Quebec G1V 0A6, Canada.|Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec G1J 2G3, Canada.
authors.forename: Martin
authors.identifier: 0000-0002-1547-3746
authors.initials: M
authors.lastname: Levesque
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, Mill Hill, NW7 1AA, United Kingdom, siew-lan.ang@crick.ac.uk.
authors.forename: Siew-Lan
authors.initials: SL
authors.lastname: Ang
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D064026:Calbindins / Q000378:metabolism; D002452:Cell Count; D003911:Dextrans / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000502:physiology; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase; D012686:Septal Nuclei / Q000166:cytology* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000196:embryology / Q000254:growth & development
chemical_list: D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D051792:Basic Helix-Loop-Helix Proteins; D001710:Biotin; D064026:Calbindins; D003911:Dextrans; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D050697:Retinal Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; C501008:Neurod1 protein, mouse; C110701:Neurod6 protein, mouse; C076397:biotinylated dextran amine; C515028:ALDH1A1 protein, mouse
keywords: Neurod1; Neurod6; lateral septum; midbrain dopaminergic neurons; neuronal diversity; ventral tegmental area