Descrizione del progetto
Il ruolo del centrosoma nella neurogenesi
Il centrosoma è un organello che funge da centro organizzativo dei microtubuli nella cellula animale ed è coinvolto in funzioni quali la divisione cellulare, la formazione e la migrazione delle ciglia. Le mutazioni nelle proteine associate ai centrosomi provocano malattie cerebrali, ma i meccanismi di questo processo non sono noti. Il progetto NeuroCentro, finanziato dall’UE, studierà le funzioni fondamentali di specifiche proteine centrosomiche neurali, al fine di comprendere il fenotipo cerebrale specifico delle mutazioni. La ricerca si avvale della recente scoperta raggiunta dal team del progetto riguardante proteine innovative correlate al centrosoma che si legano all’RNA nelle cellule staminali neurali umane, con associazioni significative e selettive all’eterotopia periventricolare, un disturbo di migrazione neuronale. Alla fine, i ricercatori cercheranno di impiegare strumenti genetici avanzati per ripristinare la funzionalità centrosomica e invertire i difetti alla base dell’eterotopia periventricolare.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
85764 Neuherberg
Germania