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Endosomal control of local protein synthesis in axons

Project description

Neuronal courier services may do more than just deliver the goods

The messenger RNA, or mRNA, carries the genetic message from the nucleus into the cytoplasm where it is translated into a protein by ribosomes. How cells regulate where and when protein synthesis occur in very complex cells such as neurons remain a very active area of research. The EU-funded AXONENDO project is building on the discovery that mRNAs and ribosomes are present on moving vesicles called endosomes in the axons of neurons, hoping to tease out the mechanisms and a potential role in development and neuronal function. Endosomal trafficking in axons and dendrites is like a neuronal courier for fast and effective point-to-point delivery of goods. Now it could also play a key role in changing local protein expression in response to extracellular factors.

Objective

Neurons are morphologically complex cells that rely on highly compartmentalized signaling to coordinate cellular functions. The endocytic pathway is a crucial trafficking route by which neurons integrate, spatially process and transfer information. Endosomal trafficking in axons and dendrites ensures that required molecules and signaling complexes are present where and when they are functionally needed thus fulfilling essential roles in neuronal physiology. Our recent work has revealed the presence of mRNAs and ribosomes on endosomes in axons, raising the exciting possibility that these motile organelles also directly modulate the local proteome by controlling de novo protein synthesis. However, the mechanisms by which endosomes regulate mRNA translation in neurons is unknown. Moreover, the roles of endosome-mediated control of protein synthesis in neuronal development and function have not been investigated. Here, we propose to bridge this knowledge gap by elucidating links between the endocytic pathway and local protein synthesis in neurons, focusing on their functional relationship in axons. By combining genome-wide analysis, genetic tools, state-of-the-art imaging techniques and the use of Xenopus and mouse vertebrate models, we plan to address the following fundamental questions: (i) What are the mRNAs associated with endosomes and does endosomal trafficking regulate their axonal localization? (ii) Does the endocytic pathway mediate the selective translation of axonal mRNAs in response to extracellular factors? (iii) What are the endosome-associated RNA-binding proteins, and what is the effect of perturbing these associations on axonal development and maintenance in vivo? (iv) Does impaired endosomal regulation of axonal mRNA localization and translation cause axonopathies? Answering these questions will set strong foundations for this new area of research and can provide a new angle in our comprehension of neuropathies in need of novel therapeutic strategies.

Host institution

OSPEDALE SAN RAFFAELE SRL
Net EU contribution
€ 1 499 563,00
Address
VIA OLGETTINA 60
20132 Milano
Italy

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Region
Nord-Ovest Lombardia Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Total cost
€ 1 499 563,00

Beneficiaries (1)