title: BMP2 and GDF5 induce neuronal differentiation through a Smad dependant pathway in a model of human midbrain dopaminergic neurons.
abstract: Parkinson's disease is the second most common neurodegenerative disease, and is characterised by the progressive degeneration of the nigrostriatal dopaminergic (DA) system. Current treatments are symptomatic, and do not protect against the DA neuronal loss. One of the most promising treatment approaches is the application of neurotrophic factors to rescue the remaining population of nigrostriatal DA neurons. Therefore, the identification of new neurotrophic factors for midbrain DA neurons, and the subsequent elucidation of the molecular bases of their effects, are important. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth differentiation factor 5 (GDF5), have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo. However, the molecular (signalling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects remain to be elucidated. Using the SH-SH5Y human neuronal cell line, as a model of human midbrain DA neurons, we have shown that GDF5 and BMP2 induce neurite outgrowth via a direct mechanism. Furthermore, we demonstrate that these effects are dependent on BMP type I receptor activation of canonical Smad 1/5/8 signalling.
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: Aideen M
authors.initials: AM
authors.lastname: Sullivan
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055428:Growth Differentiation Factor 5 / Q000494:pharmacology*; D006801:Humans; D008636:Mesencephalon / Q000166:cytology; D055495:Neurogenesis; D011994:Recombinant Proteins / Q000494:pharmacology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D055396:Bone Morphogenetic Protein 2; D055428:Growth Differentiation Factor 5; D011994:Recombinant Proteins; D051785:Smad Proteins
keywords: BMP receptor; BMP(s); BMP2; BMPR(s); DA; DIV; Dorsomorphin; GDF(s); GDF5; GDNF; MAPK; MTT; N; Neuronal differentiation; PBS; RT-PCR; SH-SY5Y cells; Smad 1/5/8; Smad signalling; Smad1, Smad5 and Smad8; TGF; VM; bone morphogenetic protein receptor(s); bone morphogenetic protein(s); caBMPRIb; constitutively active BMPRIb; day(s) in vitro; dopaminergic/dopamine; glial cell line-derived neurotrophic factor; growth differentiation factor(s); mitogen activated protein kinases; number of repetitions; phosphate buffered saline; reverse transcriptase-polymerase chain reaction; thiazolyl blue tetrazolium bromide; transforming growth factor; ventral midbrain