Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Marica Catinozzi (Donders series 504)

31 May 2021

Promotor: Prof. dr. E.J.M. Storkebaum 
Co-promotor: Dr. M. Mallik

Molecular and genetic characterization of the diverse roles of cabeza, the Drosophila homolog of human FUS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by deterioration of upper and lower motor neurons, leading to muscle weakness and paralysis, ultimately resulting in death. I focused on cabeza (caz), the Drosophila homolog of FUS/TLS. Availability of a vast repertoire of gene manipulation tools ensured that Drosophila could be used as a model system to investigate the role of the protein not only in the nervous system but also in muscles. Interestingly, loss of caz function resulted in developmental lethality while a milder phenotype was observed upon selective inactivation of the protein in adult neurons. A genetic screen of the second and third chromosomes led to the identification of Xrp1 as novel interactor of caz; a 50% reduction in Xrp1 gene dosage is sufficient to rescue the caz mutant phenotypes. Xrp1 is highly up-regulated in caz mutants and interestingly, neuron selective knock-down of Xrp1 rescues the mutant phenotypes, emphasizing a prominent role of caz in neurons. Caz mutants exhibit adult abdominal muscle defects, this adult phenotype correlates with a reduced number of founder myoblasts; selective expression of caz in myoblasts rescues the number of founder cells and muscles, suggesting that caz is required for muscle development. Selection of the founders is mediated by FGF signaling and indeed, the downstream FGF target Stumps shows reduced levels in caz mutants. Moreover, overexpression of Xrp1 strongly reduces Stumps levels in the founders. These data suggest that caz plays a role in selection of founder myoblasts by regulating Xrp1 levels.