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• W2110254575 abstract "In contrast to mammals, adult zebrafish display cellular regeneration of lost motorneurons and achieve functional recovery following a complete spinal cordtransection. Using adult zebrafish as a model to study how key developmentalpathways can be re-activated to regulate neuroregeneration in cellular recovery, Iaddressed the following questions:1) What is the role of Notch signalling during regenerative mechanisms in thelesioned spinal cord of the adult zebrafish? 2) What is the role of Notchoverexpression in neurogenesis in the adult zebrafish retina?3) Which additional signalling pathways are involved in the generation of motorneurons during spinal cord regeneration in adult zebrafish?1) In the main part of my thesis I have investigated the role of Notch signallingduring spinal cord regeneration. The Notch pathway has been shown to regulateneural progenitor maintenance and inhibit neuronal differentiation in the vertebratenervous system. In the injured mammalian spinal cord, increased Notch signallingis held partly responsible for the low regenerative potential of endogenousprogenitors to generate new neurons. However, this is difficult to test in anessentially non-regenerating system. We show that in adult zebrafish, whichexhibit lesion-induced neurogenesis, e.g. of motor neurons from endogenous spinalprogenitor cells, the Notch pathway is also reactivated. I over-activated the Notchpathway by forced expression of a heat-shock inducible active domain of notch inspinal progenitor cells. I observed that although apparently compatible withfunctional regeneration in zebrafish, forced activity of the pathwaysignificantly decreased progenitor proliferation and motor neuron generation.Conversely, pharmacological inhibition of the pathway increased proliferation andmotor neuron numbers. Thus in summary our work demonstrates that Notch is anegative signal for regenerative neurogenesis in the spinal cord.Importantly, we show for the first time that spinal motor neuron regeneration canbe augmented in an adult vertebrate by inhibiting Notch signalling.2) While in the lesioned spinal cord, over-activation of Notch attenuatedneurogenesis, I observed that in the unlesioned retina the same manipulation led tostrong proliferation of cells in the inner nuclear layer, presumable Muller glia cellswhich are the retinal progenitor cells. This coincided with an increase in eye size inadult zebrafish. These preliminary findings provide the first hint that the role ofNotch may differ for different adult progenitor cell pools and will lead to futureinvestigations 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 inthe adult lesioned spinal cord. Using in situ hybridisation, I assessed the geneexpression patterns a) for all D2-like receptors and b) candidate genes that relate tothe RA pathway in the adult lesioned spinal cord to identify the signallingcomponents.a) I found that only the D4a receptor was upregulated in spinal progenitor cells inthe ventricular zone rostral to the lesion site, but not caudal to it. This correlateswith other results showing that dopamine agonists increase motor neuronregeneration rostral, but not caudal to a spinal lesion site.b) I observed a strong increase in the expression of Cyp26a, a RA catabolisingenzyme, in the ventricular progenitor zone caudal to the lesion site, in contrast tothe weak expression rostrally. Crabp2a, a cellular retinoic acid binding protein, wasalso upregulated rostral and in close proximity to the lesion site in a subpopulationof neurons located ventrolaterally in the spinal cord.In summary, we show that the Notch pathway negatively regulates neurogenesis inthe spinal cord in contrast to the retina and provide evidence that dopamine fromthe brain signals via the D4a receptor to promote the generation of motor neuronsin addition to RA, which may also play a role in this process. These insights intoadult neural progenitor cell activation in zebrafish may ultimately informtherapeutic strategies for spinal cord injury and neurodegenerative diseases such asmotor neuron disease." @default.
• W2110254575 created "2016-06-24" @default.
• W2110254575 creator A5014642305 @default.
• W2110254575 date "2012-11-30" @default.
• W2110254575 modified "2023-09-27" @default.
• W2110254575 title "Molecular control of neurogenesis in the regenerating central nervous system of the adult zebrafish" @default.
• W2110254575 hasPublicationYear "2012" @default.
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