title: Endocytosis contributes to BMP2-induced Smad signalling and neuronal growth.
abstract: Bone morphogenetic protein 2 (BMP2) is a neurotrophic factor which induces the growth of midbrain dopaminergic (DA) neurons in vitro and in vivo, and its neurotrophic effects have been shown to be dependent on activation of BMP receptors (BMPRs) and Smad 1/5/8 signalling. However, the precise intracellular cascades that regulate BMP2-BMPR-Smad-signalling-induced neurite growth remain unknown. Endocytosis has been shown to regulate Smad 1/5/8 signalling and differentiation induced by BMPs. However, these studies were carried out in non-neural cells. Indeed, there are scant reports regarding the role of endocytosis in BMP-Smad signalling in neurons. To address this, and to further characterise the mechanisms regulating the neurotrophic effects of BMP2, the present study examined the role of dynamin-dependent endocytosis in BMP2-induced Smad signalling and neurite growth in the SH-SY5Y neuronal cell line. The activation, temporal kinetics and magnitude of Smad 1/5/8 signalling induced by BMP2 were significantly attenuated by dynasore-mediated inhibition of endocytosis in SH-SY5Y cells. Furthermore, BMP2-induced increases in neurite length and neurite branching in SH-SY5Y cells were significantly reduced following inhibition of dynamin-dependent endocytosis using dynasore. This study demonstrates that BMP2-induced Smad signalling and neurite growth is regulated by dynamin-dependent endocytosis in a model of human midbrain dopaminergic neurons.
authors.affiliation: Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Shane V
authors.initials: SV
authors.lastname: Hegarty
authors.affiliation: Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland. Electronic address: a.sullivan@ucc.ie.
authors.forename: Aideen M
authors.initials: AM
authors.lastname: Sullivan
authors.affiliation: Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland. Electronic address: g.okeeffe@ucc.ie.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
mesh_terms: D051017:Apoptosis Regulatory Proteins; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008636:Mesencephalon / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D051017:Apoptosis Regulatory Proteins; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins
keywords: BMP receptor(s); BMP(s); BMP2; BMPR(s); DA; DIV; Endocytosis; PD; Parkinson’s disease; Smad signalling; VM; bone morphogenetic protein(s); day(s) in vitro; dopaminergic; dynamin-dependent; neurite growth; ventral midbrain