Descripción del proyecto
Mecanismos de la poda sináptica en el encéfalo en desarrollo
La comunicación entre las neuronas y la microglía está mediada tanto por la formación de nuevas sinapsis como por la eliminación selectiva de conexiones innecesarias a través de la poda sináptica. Unos hallazgos recientes sugieren que la microglía elimina las conexiones superfluas y que el 70 % de las conexiones en la corteza de un primate se pierden a los seis meses de vida. Se han identificado varias señales «eat-me» o «cómeme» en la poda sináptica, pero no se han establecido señales «spare-me» o «evítame» que limiten la eliminación fagocítica. El ácido siálico del glucocáliz neuronal actúa como una señal «evítame» y previene la fagocitosis microglial a través de los receptores Siglec, y la regulación anómala del ácido siálico causa la pérdida neuronal y la mortalidad embrionaria. El objetivo del proyecto SinGly, financiado con fondos europeos, es investigar si las neuraminidasas, proteínas que reconocen el glucocáliz, tiene un desarrollo regulado y estudiar la función del ácido siálico en la poda sináptica durante el desarrollo neurológico.
Objetivo
Effective neuron-microglial communication is a prerequisite to achieve the final connectome. It is mediated by both the formation of new synapses and selective removal of unnecessary connections through synaptic pruning. Recent evidences suggest that superfluous connections are eliminated by microglia. Almost 70% of the connections are lost in a primate cortex within six months of life. But what drives this selective elimination of so many synapses is a million-euro question. Identifying neuronal signals that differentiate weak synapses from the strong ones is an emerging frontier in cellular neuroscience. Several eat-me signals in synaptic pruning have been identified, but spare-me signals that limit phagocytic elimination of synapses are yet to be explored. Sialic acids on neuronal glycocalyx acts as spare-me signal and prevents microglial phagocytosis through Siglec receptors. Aberrant regulation of sialic acid caused neuronal loss and embryonic lethality. It is also becoming evident that sialic acid plays a key role in neurodevelopment, but the cellular and molecular mechanisms by which it regulates neurodevelopment is yet to be explored. This makes sialic acid an ideal candidate to evaluate its role in neurodevelopment. Hence, we aim to interrogate whether sialidases, glycocalyx recognizing proteins are developmentally regulated and also to define sialic acid’s role in synaptic pruning during neurodevelopment. We propose to implement gene, protein expression and metabolic profiling studies to investigate whether sialidases and glycocalyx recognizing proteins are developmentally regulated. Also, we will use fluorescent azido sugars in ex vivo cultures to visualise how sialic acid regulates synaptic pruning during neurodevelopment using superresolution STED microscopy. This paves a path to identify cellular and molecular mechanisms by which glycocalyx composition defines neuron-microglia interactions and thus circuit refinement through synaptic pruning.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
01513 Vilnius
Lituania