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Novel mechanisms of neurogenesis- from centrosome to engineering migration

Project description

The centrosome's role in neurogenesis

The centrosome is an organelle that serves as the microtubule-organising centre of the animal cell and is involved in functions such as cell division, cilia formation and migration. Mutations in centrosome-associated proteins lead to brain diseases, but the mechanisms of this process are not known. The EU-funded NeuroCentro project will study fundamental functions of neural-specific centrosome proteins, aiming to understand the brain-specific phenotype of mutations. The research capitalises on a recent project team discovery of novel centrosome-associated RNA-binding proteins in human neural stem cells with significant and selective associations with periventricular heterotopia (PH), a neuronal migration disorder. In the end, researchers will attempt to apply advanced genetic tools to restore centrosome function and revert defects causing PH.

Objective

The centrosome is a crucial cellular organelle involved in many functions especially during development where it acts to regulate key processes, such as cell division, cilia formation and migration. While many mutations in centrosome-associated proteins lead to diseases often predominantly affecting the brain, the basis for this specificity is in most cases not known. Likewise, basic aspects of centrosome biology, such as the role of RNAs at the centrosome, are largely unknown. Our recent discovery of novel centrosome-associated proteins in human neural stem cells revealed specific RNA-binding proteins at the sub-distal appendages of centrosomes with significant and selective associations to periventricular heterotopia (PH), a neuronal migration disorder. This provides a unique entry point to explore, in the first part of this project, fundamental questions associated with the role of RNAs and RNA-binding proteins at the centrosome and their contribution to neurodevelopmental disorders. In the second part, we will explore changes in centrosome composition from NSCs to young migratory neurons and identify the role of the centrosome in neuronal subtype-specific migration modes using the novel centrosome protein Akna as entry point. In the third part, we will utilize our advanced tools for dCas9 multiplexed transcriptional engineering to restore centrosome function of ectopic neurons and revert migration defects causing PH. These rescue attempts will be extended to later stages of development aiming to revert differentiated glia, the ependymal cells, to radial glial cells, that serve as guides for migrating neurons. This work will thus tackle fundamental functions of neural-specific centrosome proteins, laying the basis to understand the brain-specific phenotype of mutations in factors that are widely expressed but predominantly affect the brain.

Host institution

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Net EU contribution
€ 2 256 834,00
Address
INGOLSTADTER LANDSTRASSE 1
85764 Neuherberg
Germany

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Region
Bayern Oberbayern München, Landkreis
Activity type
Research Organisations
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Total cost
€ 2 256 834,00

Beneficiaries (1)