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Fine-tuning neurogenesis : microRNA regulatory networks

2015Doctoral thesis Restricted access
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorSolá, Susana, 1976-
dc.contributor.authorMorgado, Ana Luísa Silva Neves, 1988-
dc.date.accessioned2016-03-08T12:57:50Z
dc.date.available2016-03-08T12:57:50Z
dc.date.issued2015
dc.date.submitted2015
dc.descriptionTese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2015pt_PT
dc.description.abstractNeurogenesis, the process of producing neurons from neural stem cells (NSCs) occurs in discrete areas of the adult mammalian brain. However, NSCs produce very few neurons following injury or pathological conditions. Thus, the identification of novel players that improve neurogenesis may have huge impact in the development of strategies for neural repair. Recent discoveries have revealed that microRNAs (miRNAs or miRs) have important roles in stem cell biology, controlling stem cell fate and behavior. Strikingly, additional evidence suggests the involvement of apoptosis-associated miRNAs in stem cell differentiation. Thus, our studies were conducted with the purpose of further characterizing the molecular mechanisms by which specific apoptosis-associated miRNAs regulate NSC differentiation to ultimately improve neurogenesis as an alternative to cell loss. In initial studies we evaluated the expression of specific apoptosis-associated miRNAs during the differentiation process of mouse NSCs. Validation by qRT-PCR revealed that pro-apoptotic miR-16, let-7a, let-7b, miR-34 family members, and miR- 143/145 cluster, as well as anti-apoptotic miR-21 are differentially expressed throughout NSC differentiation. We further investigated the role of two of the most modulated miRNAs. First, we assessed the impact of miR-34a during neuronal differentiation. We showed that miR- 34a is significantly downregulated during NSC differentiation and that miR-34a overexpression significantly impairs neurogenesis progression. Additionally, we demonstrated that miR-34a downregulation is crucial to allow upregulation of synaptotagmin 1 (Syt1) and autophagy-related 9a (Atg9a) proteins, essential for differentiation to progress. Finally, we explored the role of miR-145 in NSC differentiation. We discovered that neuronal differentiation was associated with a marked increase in miR-145 levels and reported that forced miR-145 downregulation negatively affects this process. Additional experiments, in turn, indicated that miR-145 regulates differentiation of mouse NSCs through the sex-determining region Y-box 2 (Sox2)– Lin28/let-7 pathway. These results demonstrate that miR-34a downregulation and miR- 145 upregulation are required for proper neuronal differentiation. In conclusion, our findings clarify the role of miR-34a and miR-145 during neuronal differentiation and may prove useful in the development of novel therapeutic strategies to improve long-term survival and differentiation of endogenous and/or transplanted stem cells.pt_PT
dc.description.provenanceSubmitted by Amelia Janeiro (ajaneiro@reitoria.ul.pt) on 2016-03-02T17:05:07Z No. of bitstreams: 1 ulsd072350_td_Ana_Morgado.pdf: 92932758 bytes, checksum: 3579d51f9b77a5ee931fd5c65d914c49 (MD5)en
dc.description.provenanceMade available in DSpace on 2016-03-08T12:57:50Z (GMT). No. of bitstreams: 1 ulsd072350_td_Ana_Morgado.pdf: 92932758 bytes, checksum: 3579d51f9b77a5ee931fd5c65d914c49 (MD5) Previous issue date: 2015en
dc.description.sponsorshipFundo Europeu de Desenvolvimento Regional (FEDER)pt_PT
dc.identifier.tid101376502
dc.identifier.urihttp://hdl.handle.net/10451/22882
dc.language.isoengpt_PT
dc.relationCONTROL OF STEM CELL FATE BY THE P53 NETWORK: DIFFERENTIATION VERSUS APOPTOSIS
dc.relationPreventing Memory Loss in Alzheimer`s Disease: Underlying Mechanisms and Therapeutic Targets of Tauroursodeoxycholic Acid
dc.relationDriving Mitochondrial Effectors of Apoptosis Toward Neural Differentiation
dc.subjectTeses de doutoramento - 2015pt_PT
dc.titleFine-tuning neurogenesis : microRNA regulatory networkspt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardTitleCONTROL OF STEM CELL FATE BY THE P53 NETWORK: DIFFERENTIATION VERSUS APOPTOSIS
oaire.awardTitlePreventing Memory Loss in Alzheimer`s Disease: Underlying Mechanisms and Therapeutic Targets of Tauroursodeoxycholic Acid
oaire.awardTitleDriving Mitochondrial Effectors of Apoptosis Toward Neural Differentiation
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F80060%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-NMC%2F117877%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIM-MED%2F0251%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FDTP%2F04138%2F2013/PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream5876
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsrestrictedAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication26df6850-845a-48d0-a57f-8870e55b6a95
relation.isProjectOfPublication12b9d16c-7089-4bab-acee-97d598d7685d
relation.isProjectOfPublicationb62518e9-7d60-42b1-8462-b5ea0955d767
relation.isProjectOfPublication3ea9d46e-a653-42ed-aa04-6630ede070cc
relation.isProjectOfPublication.latestForDiscovery3ea9d46e-a653-42ed-aa04-6630ede070cc
thesis.degree.nameDoutoramento em Farmáciapt_PT

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