Description
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. R. Jeroen Pasterkamp is an Assistant Professor at the Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands. The focus of his laboratory is directed towards understanding the molecular and intracellular signaling events involved in the formation of neuronal connections with a particular focus on the developing dopamine system. His research team concentrates on the developing mouse embryo using an integrated approach involving molecular biology, cell biology, in vivo functional proteomics, and mouse genetics. He received his PhD from the Netherlands Institute for Neurosciences (Amsterdam, The Netherlands) and did his Postdoctoral at the Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, USA. Marten Smidt is an Associate Professor at the Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands. The focus of his laboratory is directed towards understanding the developmental processes that underlie neuronal differentiation and specification. The main focus has been the development of mesodiencephalic dopamine neurons. The work includes mouse genetics, molecular genetics and molecular biology. Marten Smidt received his PhD from the University of Groningen (Groningen, The Netherlands) and did his postdoctoral at Utrecht University, Department of Medical Pharmacology, Rudolf Magnus Institute of Neuroscience (Utrecht, The Netherlands). J. Peter H. Burbach is professor of Molecular Neuroscience at Utrecht University and head of the Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. His research interests concern the role of transcription factors in development and regulation of peptidergic and dopaminergic neurons, and the molecular mechanisms of human neurodevelopmental disorders. He received his PhD from Utrecht University and did postdoctoral work at the Clinical Research Institute of Montreal, Canada. He obtained professorships in Molecular Biology and Molecular Neuroendocrinology. Since 2001 he is a Summer scientist at the Marine Biological Laboratory, Woods Hole, MA, USA. 1. Development of the Dopamine Systems in Zebrafish…… 1 Jrn Schweitzer and Wolfgang Driever Abstract…… 1 Introduction……1 Overview of Dopaminergic Development in Zebrafish…… 2 Establishment of Dopaminergic Neuronal Connectivity……4 Genetic Approaches…… 6 Signaling Requirements for dA Differentiation…… 6 Transcriptional Specification of Zebrafish dA Neurons…… 9 Integration of Pharmacology and Behavioral Analysis……11 Conclusions…… 11 2. Dopamine Systems in the Forebrain…… 15 John W. Cave and Harriet Baker Abstract…… 15 Introduction…… 15 Anatomy and Function of OB DA Neurons…… 16 OB DA Neurogenesis…… 19 Molecular Genetic Mechanisms of OB DA Neuron Differentiation…… 21 Expression and Function of Forebrain DA Receptors……28 Prospective Directions for OB DA Neurobiology…… 28 References…… 29 3. The Role of Otx genes in Progenitor Domains of Ventral Midbrain……36 Antonio Simeone, Eduardo Puelles, Dario Acampora, Daniela Omodei, Pietro Mancuso and Luca Giovanni Di Giovannantonio Abstract…… 36 Introduction…… 36 Otx genes in the Positioning of the Midbrain-Hindbrain Boundary (MHB)…… 37 Otx-Dose Dependent Control of Anterior-Posterior (A-P) and Dorso-Ventral (D-V) Patterning of the Midbrain…… 39 Otx2 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…… 47 Marten P. Smidt and J. Peter H. Burbach Introduction…… 47 Terminal Differentiation of Substantia Nigra Neurons Depends on the Homeobox Gene Pitx3…… 47 Nurr1 is Essential for Generating the Full Dopaminergic Phenotype of Mesodiencephalic Dopaminergic Neurons…… 52 Concluding Remarks…… 54 5. Foxa1 and Foxa2 Transcription Factors RegulateDifferentiation of Midbrain Dopaminergic Neurons…… 58 Siew-Lan Ang Abstract…… 58 Introduction…… 58 Expression of Foxa1/2 Proteins in the CNS……59 Cross-Regulatory Roles of Foxa2 and Shh and Early Functions of Foxa2 in Dorsal-Ventral Patterning of the CNS…… 59 A Role for Foxa1/2 in Neuronal Specification of the Midbrain Floor Plate…… 60 Foxa1/2 are also Required for the Generation of Immature and Mature mDA Neurons…… 60 Mechanims of Foxa Gene Regulation: Examples from Endodermal Organs…… 61 Concluding Remarks…… 63 6. Transcriptional Regulation of their Survival: The Engrailed Homeobox Genes…… 66 Horst H. Simon and Kambiz N. Alavian The Engrailed Genes……66 Molecular Structure and Properties of the Engrailed Proteins…… 66 The Engrailed Genes and Mesencephalic Dopaminergic (mesDA) Neurons (Early)…… 67 The engrailed Genes and Mesencephalic Dopaminergic Neurons (Later)…… 68 7. Neurotrophic Support of Midbrain Dopaminergic Neurons…… 73 Oliver von Bohlen und Halbach and Klaus Unsicke Abstract…… 73 Introduction…… 73 Neurotrophins…… 74 Fibroblast Growth Factors (FGFs)…… 75 Other Factors…… 77 Future Directions…… 77 8. TGF- in Dopamine Neuron Development, Maintenance and Neuroprotection…… 81 Eleni Roussa, O. von Bohlen und Halbach and K. Krieglstein Abstract…… 81 Introduction…… 81 Evidence for TGF- Effects on the Induction of Dopaminergic Neurons in Vitro…… 82 Evidence for TGF- Effects on the Induction of Dopaminergic Neurons in Vivo…… 83 TGF- Superfamily Members and Induction of Dopaminergic Neurons…… 84 TGF- Promotes Survival of DAergic Neurons…… 85 GDNF Promotes Survival of DAergic Neurons…… 85 TGF- and GDNF Cooperate to Promote Survival and Protection of DAergic Neurons…… 86 Conserved Dopamine Neurotrophic
