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Mechanism of action of ARHGEF10, a conserved gene linked to neurodevelopmental disorders
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Resumo(s)
The Rho guanine nucleotide exchange factor 10 (ARHGEF10) is a guanine exchange factor
(GEF) from the DBL family involved in the activation of the Rho family of small GTPases (Rho
GTPases) from the Rho subfamily by accelerating the exchange of guanosine diphosphate (GDP) for
guanosine triphosphate (GTP). ARHGEF10 participates in several cellular mechanisms, such as the
regulation of cell contractility, membrane trafficking, cell migration, and cell-cell tight junctions.
Several mutations in ARHGEF10 have indicated that it is linked with peripheral and central
neurodevelopmental disorders associated with locomotor and behavioral dysfunctions in several
organisms, namely slowed nerve conduction velocity associated with thin myelin fibers, developmental
delay, motor coordination problems, attention deficit, hyperactivity, aggressiveness, epilepsy, and
schizophrenia in humans; peripheral neuropathies in humans and dogs; Autism Spectrum Disorder
(ASD) in mice; and locomotor abnormalities in zebrafish larvae. However, the molecular and cellular
mechanisms linking the gene to the behavior effects are unclear.
In this thesis, we followed up a preliminary finding from our group that locomotor
abnormalities were present in Drosophila melanogaster ARHGEF10 (darhgef10) mutants, indicating
that the role of ARHGEF10 in controlling locomotor function could be conserved across animals, to
gain insight into the cellular basis of the D. melanogaster darhgef10 mutant locomotor phenotype.
Using two different methods to characterize the fly locomotor behavior, we found that both sex mutants
showed impaired locomotor behavior that is, however, more pronounced in males than in females. Male
cell-specific darhgef10 knockdown indicated that the impaired fly locomotor activity caused by the
darhgef10 deletion could be better explained by the neuronal rather than the glial darhgef10
knockdown. Finally, the darhgef10-dependent locomotor phenotype rescue attempt revealed no rescue
and distinct spontaneous locomotor behavior phenotypes between the sexes. The differences between
gender locomotor behaviors observed for all experiments suggest that darhgef10 may have specialized
sex-specific functions.
Descrição
Tese de mestrado, Biologia Humana e Ambiente, 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
dArhgef10 Comportamento locomotor Drosophila melanogaster Células gliais Neurónios Teses de mestrado - 2024