title: Canonical BMP-Smad signalling promotes neurite growth in rat midbrain dopaminergic neurons.
abstract: Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson's disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway.
authors.affiliation: Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Shane V
authors.initials: SV
authors.lastname: Hegarty
authors.forename: Louise M
authors.initials: LM
authors.lastname: Collins
authors.forename: Aisling M
authors.initials: AM
authors.lastname: Gavin
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Roche
authors.forename: Sean L
authors.initials: SL
authors.lastname: Wyatt
authors.forename: Aideen M
authors.initials: AM
authors.lastname: Sullivan
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000196:embryology / Q000254:growth & development; D059290:Dopaminergic Neurons / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055428:Growth Differentiation Factor 5 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D016501:Neurites / Q000648:ultrastructure*; D055495:Neurogenesis / Q000502:physiology; D011720:Pyrazoles; D011743:Pyrimidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology*; D013378:Substantia Nigra / Q000196:embryology / Q000254:growth & development; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D002352:Carrier Proteins; D055428:Growth Differentiation Factor 5; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; D051785:Smad Proteins; D014446:Tyrosine 3-Monooxygenase; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525720:Bmp2 protein, rat; C000594129:GDF5 protein, rat; C516138:dorsomorphin