Publicação
Functional analysis of the notch signalling cascade in neural progenitors
| Resumo: | With the ageing of world population, the number of people suffering from neuronal degeneration is drastically increasing and new strategies to prevent or cure neurodegenerative diseases are urgently needed. One exciting avenue is the use of stem cells to replace damaged neural tissues, but this requires a more comprehensive understanding of the molecular events regulating nervous system development. In this thesis, I have investigated one molecular pathway that orchestrates vertebrate neural development: the Notch signalling pathway. Notch activity is known to restrain neuronal differentiation, maintaining a pool of neural progenitors throughout development to ensure the production of correct number and types of neurons. During differentiation, various mechanisms exist to modulate Notch activity and my work highlights how two particular HES proteins function to terminate Notch signalling in newborn neurons of the chick embryo: while HES6-2 represses transcription of genes encoding Notch effectors, HES6-1 acts to sequester and inactivate these effectors. I have also generated a novel reporter to monitor Notch signalling in neural progenitors at the single-cell level. A correlation was observed between the timing of Notch activation and the cell cycle of neural progenitors, supporting a model for how Notch signalling regulates neural fate decisions. When the pathway is active during mitosis, progenitor-generating divisions are favoured, whereas absence of Notch activity in mitotic progenitors might lead to different daughter cell fates. My work provides new insights into the role of Notch signalling in neural progenitors during vertebrate nervous system development, and how differentiating neurons terminate Notch activity. This knowledge is important to design novel strategies to control neural differentiation and might lead to future applications in regenerative medicine of the adult nervous system. |
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| Autores principais: | Vilas-Boas, Filipe, 1983- |
| Assunto: | Receptores Notch Medula espinal Neurogénese Genes reporter Transcrição genética Factores de transcrição Expressão génica Pâncreas Teses de doutoramento - 2011 |
| Ano: | 2011 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | With the ageing of world population, the number of people suffering from neuronal degeneration is drastically increasing and new strategies to prevent or cure neurodegenerative diseases are urgently needed. One exciting avenue is the use of stem cells to replace damaged neural tissues, but this requires a more comprehensive understanding of the molecular events regulating nervous system development. In this thesis, I have investigated one molecular pathway that orchestrates vertebrate neural development: the Notch signalling pathway. Notch activity is known to restrain neuronal differentiation, maintaining a pool of neural progenitors throughout development to ensure the production of correct number and types of neurons. During differentiation, various mechanisms exist to modulate Notch activity and my work highlights how two particular HES proteins function to terminate Notch signalling in newborn neurons of the chick embryo: while HES6-2 represses transcription of genes encoding Notch effectors, HES6-1 acts to sequester and inactivate these effectors. I have also generated a novel reporter to monitor Notch signalling in neural progenitors at the single-cell level. A correlation was observed between the timing of Notch activation and the cell cycle of neural progenitors, supporting a model for how Notch signalling regulates neural fate decisions. When the pathway is active during mitosis, progenitor-generating divisions are favoured, whereas absence of Notch activity in mitotic progenitors might lead to different daughter cell fates. My work provides new insights into the role of Notch signalling in neural progenitors during vertebrate nervous system development, and how differentiating neurons terminate Notch activity. This knowledge is important to design novel strategies to control neural differentiation and might lead to future applications in regenerative medicine of the adult nervous system. |
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