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Zanarella, Erica (2011) Functional analysis of EFHC1, a gene involved in Juvenile Myoclonic Epilepsy, in Drosophila. [Ph.D. thesis]

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Abstract (english)

Mutations in the EFHC1 gene, encoding a novel microtubule binding protein, have been linked to juvenile myoclonic epilepsy. EFHC1 has been proposed to regulate cell division by controlling mitotic spindle organization and cerebral cortex lamination by modulating neuroblast migration. To understand EFHC1 function in vivo we generated knock-out Drosophila for the fly homolog Defhc1. We found that the NMJ synapse of Defhc1 mutants display an increased number of satellite boutons and increased spontaneous neurotransmitter release. Defhc1 binds to microtubules in vitro and overlaps in vivo with axonal and synaptic microtubules. Elimination of Defhc1 from synaptic terminals reduces the number of microtubule loops, whose presence correlates with halted bouton division, suggesting that Defhc1 is a negative regulator of bouton division. These results suggest that Defhc1 functions as an inhibitor of neurite growth by finely tuning the microtubule cytoskeleton dynamics and that EFHC1-dependent JME may result from augmented spontaneous neurotransmitter release due to overgrowth of neuronal processes.

Abstract (italian)

Mutazioni nel gene EFHC1, che codifica per una proteina in grado di legarsi ai microtubuli, sono state correlate con l’insorgenza dell’Epilessia Mioclonica Giovanile (JME). Il gene EFHC1 è stato proposto come regolatore della divisione cellulare attraverso il controllo dell’organizzazione del fuso mitotico e come modulatore della migrazione dei neuroblasti nella corteccia cerebrale. Per comprendere in vivo la funzione del gene EFHC1 abbiamo generato il mutante knock-out per il gene omologo Defhc1 in Drosophila. Le sinapsi di giunzioni neuromuscolari (NMJ) di larve mutanti per Defhc1 mostrano un maggior numero di bottoni satellite e l’aumento del rilascio spontaneo di neurotrasmettitore. Esperimenti in vitro hanno dimostrato che la proteina Defhc1 si lega ai microtubuli e che in vivo colocalizza con i microtubuli sinaptici e assonali. In seguito all’eliminazione di Defhc1 dalle terminazioni sinaptiche è stata osservata una diminuzione del numero di loops formati dai microtubuli, la cui presenza è correlata con il blocco della divisione dei bottoni sinaptici, suggerendo che il gene Defhc1 possa essere un regolatore negativo della divisione dei bottoni sinaptici. Questi risultati suggeriscono che Defhc1, attraverso una fine regolazione della dinamicità dei microtubuli del citoscheletro, agisca da inibitore della crescita delle terminazioni sinaptiche tramite e che la JME dipendente da mutazione di EFHC1 potrebbe dipendere da un aumento del rilascio spontaneo di neurotrasmettitore conseguente all’eccessiva crescita sinaptica.

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EPrint type:Ph.D. thesis
Tutor:Cignarella, Andrea
Supervisor:Daga, Andrea
Ph.D. course:Ciclo 23 > Scuole per il 23simo ciclo > SCIENZE FARMACOLOGICHE > FARMACOLOGIA, TOSSICOLOGIA E TERAPIA
Data di deposito della tesi:UNSPECIFIED
Anno di Pubblicazione:28 January 2011
Key Words:Drosophila, giunzione neuromuscolare, microtubuli
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/18 Genetica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Farmacologia ed Anestesiologia "E. Meneghetti"
Codice ID:3707
Depositato il:21 Jul 2011 11:12
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