Novel molecular mechanisms involved in neuronal migration during cortical development
[eng] The cerebral cortex is an evolutionarily advanced brain structure that processes sensory, motor and cognitive information. Its complex organization reflects the differentiation patterns and cell migration that take place during embryogenesis. During embryonic development, newly formed neurons...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Oviedo (UNIOVI) |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/224380 |
| Acceso en línea: | https://hdl.handle.net/2445/224380 http://hdl.handle.net/10803/695768 |
| Access Level: | acceso embargado |
| Palabra clave: | Neurociències Migració cel·lular Neurobiologia del desenvolupament Escorça cerebral Axons Neurosciences Cell migration Developmental neurobiology Cerebral cortex |
| Sumario: | [eng] The cerebral cortex is an evolutionarily advanced brain structure that processes sensory, motor and cognitive information. Its complex organization reflects the differentiation patterns and cell migration that take place during embryogenesis. During embryonic development, newly formed neurons travel from their place of origin in the ventricular zone, where neuronal stem cells are located, to their final positions in the cortical plate, where they form synaptic connections with other neurons. This process is essential for establishing the laminar and functional organization of the cortex, and any alteration in it can have a significant impact in the proper function of the brain. Cortical migration relies on the delicate balance of intercellular adhesive and repulsive signaling that takes place between neurons interacting with different substrates and guidance cues. Here, we attempt to provide a comprehensive understanding of some novel molecular interactions of guidance receptors that act in early development to regulate cortical migration. For this purpose, we used well-established migration assays and microfluidic systems, as well as profiling experiments (transcriptomic and proteomic) and gain- and loss-of-function experiments to study the role of some synaptic proteins that act as guidance receptors at these early developmental stages. We also coupled structure-based protein engineering to in vivo gene editing and fluorescence shadow imaging to probe the importance of these interactions in cortical migration. First, we have defined the role of GPC3-Unc5 receptor complex in cell migration. The results demonstrate a conserved structural mechanism of cell guidance in different biological contexts. Second, we have described the impact of LRRTM4 and GPC4 on cortical migration by a contact repulsion-dependent mechanism. Moreover, by taking advantage of artificial intelligence systems we were able to predict the 3D structures and the interaction model. Third, we have shown how Teneurin directs neuronal migration switching between homophilic and Latrophilin binding. Our results showcase how a single receptor employs mutually exclusive structural mechanisms to finely tune neuronal migration. In summary, these findings can now lead to a better understanding of the molecular mechanisms controlling neural migration. Studying how cortex is formed and expanded during development can help to understand the pathophysiology of several neurological diseases associated with alterations in this process, such as schizophrenia, epilepsy, autism, and bipolar disorders. |
|---|