Characterisation of the role of canonical BMP-Smad 1/5/8 signalling in the development of ventral midbrain dopaminergic neurons

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dc.contributor.advisor Sullivan, Aideen M. en
dc.contributor.advisor O'Keeffe, Gerard W. en Hegarty, Shane V. 2015-09-15T16:40:08Z 2015-09-15T16:40:08Z 2013 2014
dc.identifier.citation Hegarty, S. V. 2013. Characterisation of the role of canonical BMP-Smad 1/5/8 signalling in the development of ventral midbrain dopaminergic neurons. PhD Thesis, University College Cork. en
dc.identifier.endpage 296
dc.description.abstract Ventral midbrain (VM) dopaminergic (DA) neurons, which project to the dorsal striatum via the nigrostriatal pathway, are progressively degenerated in Parkinson’s disease (PD). The identification of the instructive factors that regulate midbrain DA neuron development, and the subsequent elucidation of the molecular bases of their effects, is vital. Such an understanding would facilitate the generation of transplantable DA neurons from stem cells and the identification of developmentally-relevant neurotrophic factors, the two most promising therapeutic approaches for PD. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth/differentiation factor (GDF) 5, which signal via a canonical Smad 1/5/8 signalling pathway, have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo, and may function to regulate VM DA neuronal development. However, the molecular (signalling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects remain to be elucidated. The present thesis hypothesised that canonical Smad signalling mediates the direct effects of BMP2 and GDF5 on the development of VM DA neurons. By activating, modulating and/or inhibiting various components of the BMP-Smad signalling pathway, this research demonstrated that GDF5- and BMP2-induced neurite outgrowth from midbrain DA neurons is dependent on BMP type I receptor activation of the Smad signalling pathway. The role of glial cell-line derived neurotrophic factor (GDNF)-signalling, dynamin-dependent endocytosis and Smad interacting protein-1 (Sip1) regulation, in the neurotrophic effects of BMP2 and GDF5 were determined. Finally, the in vitro development of VM neural stem cells (NSCs) was characterised, and the ability of GDF5 and BMP2 to induce these VM NSCs towards DA neuronal differentiation was investigated. Taken together, these experiments identify GDF5 and BMP2 as novel regulators of midbrain DA neuronal induction and differentiation, and demonstrate that their effects on DA neurons are mediated by canonical BMPR-Smad signalling. en
dc.description.sponsorship Irish Research Council for Science Engineering and Technology (R13702 IRCSET Embark Postgraduate Scholarship) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Shane V. Hegarty en
dc.rights.uri en
dc.subject Bone morphogenetic proteins en
dc.subject Growth/differentiation factor 5 en
dc.subject Ventral midbrain en
dc.subject Canonical Smad signalling en
dc.subject Nervous system development en
dc.subject Dopaminergic neuron en
dc.title Characterisation of the role of canonical BMP-Smad 1/5/8 signalling in the development of ventral midbrain dopaminergic neurons en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text available en No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.description.status Not peer reviewed en
dc.internal.copyrightchecked !!CORA!! 15 Sep 2015. Published versions of journal articles included from Springer and Elsevier. Checked policies of both publishers. For Elsevier published journal articles "Theses and dissertations which contain embedded PJAs as part of the formal submission can be posted publicly by the awarding institution with DOI links back to the formal publications on ScienceDirect" Accessed [15 Sep 2015]. For Springer copyright transfer agreement "Author retains the right to use his/her article for his/her further scientific career by including the final published journal article in other publications such as dissertations and postdoctoral qualifications provided acknowledgement is given to the original source of publication." Accessed 15 Sep 2015 Anatomy en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out No en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
dc.internal.conferring Summer Conferring 2014

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