Theneurotransmitter dopamine has just celebrated its 50thbirthday. The discovery of dopamine as a neuronal entity in the late 1950s and the notion that it serves in neurotransmission has been a milestone in the field of neuroscience research. This milestone marked the beginning of an era that explored the brain as an integrated collection of neuronal systems that one could distinguish on basis of neurotransm- ter identities, and importantly, in which one started to be able to pinpoint the seat of brain disease. The mesodiencephalic dopaminergic (mdDA) system, previously designated as midbraindopaminergic system, has received much attention since its discovery. The initial identification of dopamine as a neurotransmitter in the central nervous system (CNS) and its relevance to psychiatric and neurological disorders have stimulated a plethora of neurochemical, pharmacological and genetic studies into the function of dopamine neurons and theirprojections. In the last decade, studies on gene expression and development have further increased the knowledge of this neuronal population and have unmasked a new level of complexity. The start of the molecular dissection of the mdDA system has been marked by the cloning and characterization ofNurrl and Pitx3. These transcription factors were shown to have a critical function during mdDA development. These initial studies have been followed by the identification of many other proteins, which have a crucial function in the creation of a dopamine neuron permissive region, induction of precursors, induction of terminaldifferent- tion and finally maintenance of the mdDA neuronal pool.

1. Development of the Dopamine Systems in Zebrafish...... 1Jörn Schweitzer and Wolfgang Driever Abstract...... 1Introduction......1Overview of Dopaminergic Development in Zebrafish...... 2Establishment of Dopaminergic Neuronal Connectivity......4Genetic Approaches...... 6Signaling Requirements for dA Differentiation...... 6Transcriptional Specification of Zebrafish dA Neurons...... 9Integration of Pharmacology and Behavioral Analysis......11Conclusions...... 11 2. Dopamine Systems in the Forebrain...... 15John W. Cave and Harriet Baker Abstract...... 15Introduction...... 15Anatomy and Function of OB DA Neurons...... 16OB DA Neurogenesis...... 19Molecular Genetic Mechanisms of OB DA Neuron Differentiation...... 21Expression and Function of Forebrain DA Receptors......28Prospective Directions for OB DA Neurobiology...... 28References...... 29 3. The Role of Otx genes in Progenitor Domains of Ventral Midbrain......36Antonio Simeone, Eduardo Puelles, Dario Acampora, Daniela Omodei, Pietro Mancuso and Luca Giovanni Di Giovannantonio Abstract...... 36Introduction...... 36Otx genes in the Positioning of the Midbrain-Hindbrain Boundary (MHB)...... 37Otx-Dose Dependent Control of Anterior-Posterior (A-P) and Dorso-Ventral (D-V) Patterning of the Midbrain...... 39Otx2 Regulates Extent, Identity and Fate of Progenitor Domains in the Ventral Midbrain...... 41 4. Terminal Differentiation of Mesodiencephalic Dopaminergic Neurons: the role of Nurr1 and Pitx3...... 47Marten P. Smidt and J. Peter H. Burbach Introduction...... 47Terminal Differentiation of Substantia Nigra Neurons Depends on the Homeobox Gene Pitx3...... 47Nurr1 is Essential for Generating the Full Dopaminergic Phenotype of Mesodiencephalic Dopaminergic Neurons...... 52Concluding Remarks...... 54 5. Foxa1 and Foxa2 Transcription Factors RegulateDifferentiation of Midbrain Dopaminergic Neurons...... 58Siew-Lan Ang Abstract...... 58Introduction...... 58Expression of Foxa1/2 Proteins in the CNS......59Cross-Regulatory Roles of Foxa2 and Shh and Early Functions of Foxa2 in Dorsal-Ventral Patterning of the CNS...... 59A Role for Foxa1/2 in Neuronal Specification of the Midbrain Floor Plate...... 60Foxa1/2 are also Required for the Generation of Immature and Mature mDA Neurons...... 60Mechanims of Foxa Gene Regulation: Examples from Endodermal Organs...... 61Concluding Remarks...... 63 6. Transcriptional Regulation of their Survival: The Engrailed Homeobox Genes...... 66Horst H. Simon and Kambiz N. Alavian The Engrailed Genes......66Molecular Structure and Properties of the Engrailed Proteins...... 66The Engrailed Genes and Mesencephalic Dopaminergic (mesDA) Neurons (Early)...... 67The engrailed Genes and Mesencephalic Dopaminergic Neurons (Later)...... 68 7. Neurotrophic Support of Midbrain Dopaminergic Neurons...... 73Oliver von Bohlen und Halbach and Klaus Unsicke Abstract...... 73Introduction...... 73Neurotrophins...... 74Fibroblast Growth Factors (FGFs)...... 75Other Factors...... 77Future Directions...... 77 8. TGF-ß in Dopamine Neuron Development, Maintenance and Neuroprotection...... 81Eleni Roussa, O. von Bohlen und Halbach and K. Krieglstein Abstract...... 81Introduction...... 81Evidence for TGF-ß Effects on the Induction of Dopaminergic Neurons in Vitro...... 82Evidence for TGF-ß Effects on the Induction of Dopaminergic Neurons in Vivo...... 83TGF-ß Superfamily Members and Induction of Dopaminergic Neurons...... 84TGF-ß Promotes Survival of DAergic Neurons...... 85GDNF Promotes Survival of DAergic Neurons...... 85TGF-ß and GDNF Cooperate to Promote Survival and Protection of DAergic Neurons...... 86Conserved Dopamine Neurotrophic