title: DeltaA/DeltaD regulate multiple and temporally distinct phases of notch signaling during dopaminergic neurogenesis in zebrafish.
abstract: Dopaminergic neurons develop at distinct anatomical sites to form some of the major neuromodulatory systems in the vertebrate brain. Despite their relevance in neurodegenerative diseases and the interests in reconstitutive therapies from stem cells, mechanisms of the neurogenic switch from precursor populations to dopaminergic neurons are not well understood. Here, we investigated neurogenesis of different dopaminergic and noradrenergic neuron populations in the zebrafish embryo. Birth-dating analysis by EdU (5-ethynyl-2'-deoxyuridine) incorporation revealed temporal dynamics of catecholaminergic neurogenesis. Analysis of Notch signaling mutants and stage-specific pharmacological inhibition of Notch processing revealed that dopaminergic neurons form by temporally distinct mechanisms: dopaminergic neurons of the posterior tuberculum derive directly from neural plate cells during primary neurogenesis, whereas other dopaminergic groups form in continuous or wavelike neurogenesis phases from proliferating precursor pools. Systematic analysis of Notch ligands revealed that the two zebrafish co-orthologs of mammalian Delta1, DeltaA and DeltaD, control the neurogenic switch of all early developing dopaminergic neurons in a partially redundant manner. DeltaA/D may also be involved in maintenance of dopaminergic precursor pools, as olig2 expression in ventral diencephalic dopaminergic precursors is affected in dla/dld mutants. DeltaA/D act upstream of sim1a and otpa during dopaminergic specification. However, despite the fact that both dopaminergic and corticotropin-releasing hormone neurons derive from sim1a- and otpa-expressing precursors, DeltaA/D does not act as a lineage switch between these two neuronal types. Rather, DeltaA/D limits the size of the sim1a- and otpa-expressing precursor pool from which dopaminergic neurons differentiate.
authors.affiliation: Developmental Biology, Institute Biology I, Faculty of Biology, University of Freiburg, and Freiburg Institute for Advanced Studies, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mahler
authors.forename: Alida
authors.initials: A
authors.lastname: Filippi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Driever
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D002453:Cell Cycle / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051880:Receptors, Notch / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003346:Corticotropin-Releasing Hormone; D003857:Deoxyuridine; D004151:Dipeptides; D004298:Dopamine; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; D029961:Zebrafish Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C491092:Sim1a protein, zebrafish; C064045:delta protein; C468126:dld protein, zebrafish; C515950:orthopedia protein, zebrafish; C471932:mib1 protein, zebrafish; C031086:5-ethynyl-2'-deoxyuridine