Unravelling the roles of an alternatively spliced microexon in Daam1 in nervous system development and function
Microexons are an unusual form of alternative splicing with high evolutionary conservation, however, their functions are still far from being understood. In this thesis, we focused on a neuronal-specific microexon that modulates the structure of the FH2 domain of DAAM1, a protein important for actin...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/674108 |
| Acceso en línea: | http://hdl.handle.net/10803/674108 |
| Access Level: | acceso abierto |
| Palabra clave: | Synapse Actin Formin Microexon Splicing sinapsis Actina Formina Microexón Empalme 616.8 |
| Sumario: | Microexons are an unusual form of alternative splicing with high evolutionary conservation, however, their functions are still far from being understood. In this thesis, we focused on a neuronal-specific microexon that modulates the structure of the FH2 domain of DAAM1, a protein important for actin dynamics. We demonstrated that microexon inclusion directly impacts actin nucleation and polymerization capabilities of the FH2 domain, suggesting a modulatory effect on DAAM1´s function. Actin dynamics is an important factor in neuronal differentiation and function. Our studies demonstrated higher neuronal activity upon microexon removal, both in an in vitro system of differentiated glutamatergic neurons and in vivo, in a microexon KO mouse model. This presumably synaptic-driven phenotype translated into further developmental imbalances in young mice, and later on, motor and learning impairments in adulthood. These results thus reveal a highly conserved and splicing-driven control mechanism of neuronal functioning, involved in higher cognitive abilities. |
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