Combinatorial perspective on the gene expression circuits established by the CPEB-family of RNA binding proteins
[eng] The complex changes that take place in the mature Xenopus oocyte and early embryo are orchestrated in the absence of transcription. Until zygotic transcription starts, after the mid-blastula transition, cells rely on tight spatiotemporal translational regulation. Some maternal mRNAs accumulate...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/183569 |
| Acceso en línea: | https://hdl.handle.net/2445/183569 http://hdl.handle.net/10803/673591 |
| Access Level: | acceso abierto |
| Palabra clave: | Embriologia Cicle cel·lular Meiosi Embryology Cell cycle Meiosis |
| Sumario: | [eng] The complex changes that take place in the mature Xenopus oocyte and early embryo are orchestrated in the absence of transcription. Until zygotic transcription starts, after the mid-blastula transition, cells rely on tight spatiotemporal translational regulation. Some maternal mRNAs accumulate during oocyte growth and are stored, translationally silent. Upon stimuli, stored, silenced mRNAs become cytoplasmically polyadenylated and, subsequently, engage in translation. The timing and extent of translational activation are dictated by a complex code of 3’UTR motifs recognized by RNA-binding proteins. In meiotic maturation, at least three sequential polyadenylation waves occur. First, in response to progesterone, a single Aurora kinase A phosphorylation triggers CPEB1-directed cytoplasmic polyadenylation of mRNAs that are required for Cdk1 activation and meiotic progression. Second, activated Cdk1 targets CPEB1 for degradation, triggering a second polyadenylation surge that is necessary for the MI-MII transition. Last, CPEB4, synthesized from the first wave and activated by Cdk1 and ERK2 upon meiotic progression, drives a third wave during the second meiotic division that is required for the metaphase-II arrest. Unlike the well-studied roles of CPEB1 and CPEB4, the roles of the remaining family members, CPEB2 and CPEB3, remain uncharacterized. In this thesis we have performed a systematic investigation of the CPEB-family of RBPs in meiotic maturation in order to elucidate their combinatorial contribution to gene expression regulation. We have determined that CPEB1 and the CPEB2-4 subfamily differ in their expression dynamics, concentration and regulation. Like CPEB4, CPEB2 and CPEB3 are regulated by N-terminal hyperphosphorylation that causes dissolution of the CPEB-condensates. Furthermore, we have found that all CPEBs co-localize and are proximal to mRNA repression and storage proteins, probably reflecting their inclusion within large repressive mRNPs in the oocyte. We have also found that all CPEBs bind a highly overlapping subset of mRNAs, although CPEB1 and CPEB2-4 could differentially regulate a small subset of targets. All in all, we have contributed to the understanding of how the multiple CPEBs co-exist and how their activities are coordinated in the cell to dictate complex expression patterns. |
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