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dc.contributor.advisorBecker, Catherina
dc.contributor.advisorLowell, Sally
dc.contributor.authorDias, Tatyana Beverly
dc.date.accessioned2015-02-03T15:29:38Z
dc.date.available2015-02-03T15:29:38Z
dc.date.issued2012-11-30
dc.identifier.urihttp://hdl.handle.net/1842/9906
dc.description.abstractIn contrast to mammals, adult zebrafish display cellular regeneration of lost motor neurons and achieve functional recovery following a complete spinal cord transection. Using adult zebrafish as a model to study how key developmental pathways can be re-activated to regulate neuroregeneration in cellular recovery, I addressed the following questions: 1) What is the role of Notch signalling during regenerative mechanisms in the lesioned spinal cord of the adult zebrafish? 2) What is the role of Notch overexpression in neurogenesis in the adult zebrafish retina? 3) Which additional signalling pathways are involved in the generation of motor neurons during spinal cord regeneration in adult zebrafish? 1) In the main part of my thesis I have investigated the role of Notch signalling during spinal cord regeneration. The Notch pathway has been shown to regulate neural progenitor maintenance and inhibit neuronal differentiation in the vertebrate nervous system. In the injured mammalian spinal cord, increased Notch signalling is held partly responsible for the low regenerative potential of endogenous progenitors to generate new neurons. However, this is difficult to test in an essentially non-regenerating system. We show that in adult zebrafish, which exhibit lesion-induced neurogenesis, e.g. of motor neurons from endogenous spinal progenitor cells, the Notch pathway is also reactivated. I over-activated the Notch pathway by forced expression of a heat-shock inducible active domain of notch in spinal progenitor cells. I observed that although apparently compatible with functional regeneration in zebrafish, forced activity of the pathway significantly decreased progenitor proliferation and motor neuron generation. Conversely, pharmacological inhibition of the pathway increased proliferation and motor neuron numbers. Thus in summary our work demonstrates that Notch is a negative signal for regenerative neurogenesis in the spinal cord. Importantly, we show for the first time that spinal motor neuron regeneration can be augmented in an adult vertebrate by inhibiting Notch signalling. 2) While in the lesioned spinal cord, over-activation of Notch attenuated neurogenesis, I observed that in the unlesioned retina the same manipulation led to strong proliferation of cells in the inner nuclear layer, presumable Müller glia cells which are the retinal progenitor cells. This coincided with an increase in eye size in adult zebrafish. These preliminary findings provide the first hint that the role of Notch may differ for different adult progenitor cell pools and will lead to future investigations of Notch induced neurogenesis in the retina. 3) We have evidence from previous studies that the dopamine and retinoic acid (RA) signalling pathways may be involved in the generation of motor neurons in the adult lesioned spinal cord. Using in situ hybridisation, I assessed the gene expression patterns a) for all D2-like receptors and b) candidate genes that relate to the RA pathway in the adult lesioned spinal cord to identify the signalling components. a) I found that only the D4a receptor was upregulated in spinal progenitor cells in the ventricular zone rostral to the lesion site, but not caudal to it. This correlates with other results showing that dopamine agonists increase motor neuron regeneration rostral, but not caudal to a spinal lesion site. b) I observed a strong increase in the expression of Cyp26a, a RA catabolising enzyme, in the ventricular progenitor zone caudal to the lesion site, in contrast to the weak expression rostrally. Crabp2a, a cellular retinoic acid binding protein, was also upregulated rostral and in close proximity to the lesion site in a subpopulation of neurons located ventrolaterally in the spinal cord. In summary, we show that the Notch pathway negatively regulates neurogenesis in the spinal cord in contrast to the retina and provide evidence that dopamine from the brain signals via the D4a receptor to promote the generation of motor neurons in addition to RA, which may also play a role in this process. These insights into adult neural progenitor cell activation in zebrafish may ultimately inform therapeutic strategies for spinal cord injury and neurodegenerative diseases such as motor neuron disease.en_US
dc.contributor.sponsorUniversity of Edinburgh Overseas Research Scholarship Awarden_US
dc.contributor.sponsorUniversity of Edinburgh College of Medicine & Veterinary Medicine scholarshipen_US
dc.contributor.sponsorBiotechnology and Biological Sciences Research Council (BBSRC)en_US
dc.contributor.sponsorRobert Packard Centreen_US
dc.language.isoenen_US
dc.publisherThe University of Edinburghen_US
dc.relation.hasversionKuscha V, Frazer S, Dias T, Hibi M, Becker T, Becker C (2012) Lesion-induced generation of interneuron cell types in specific dorso-ventral domains in the spinal cord of adult zebrafish. J Comp Neurol.en_US
dc.relation.hasversionBridge KE, Berg N, Adalbert R, Babetto E, Dias T, Spillantini MG, Ribchester RR, Coleman MP. 2009. Late onset distal axonal swelling in YFP-H transgenic mice. Neurobiol Aging 30(2): 309-21en_US
dc.relation.hasversionDias T, Becker T, Becker C. Notch signaling in motor neuron regeneration in the lesioned spinal cord of adult zebrafish. 2009. Amyotrophic Lateral Sclerosis. Nov; 10 (1)en_US
dc.subjectNotchen_US
dc.subjectzebrafishen_US
dc.subjectspinal corden_US
dc.subjectstem cellsen_US
dc.subjectmotor neuronsen_US
dc.titleMolecular control of neurogenesis in the regenerating central nervous system of the adult zebrafishen_US
dc.typeThesis or Dissertationen_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US


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