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Investigating the impact of Doublecortin X (DCX) pathogenic mutants on microtubule polymerization and bundling
Author(s) -
Moslehi Maryam,
Ng Dominic C.H.,
Bogoyevitch Marie A.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1120.1
Subject(s) - doublecortin , microtubule , mutant , microbiology and biotechnology , biology , tubulin , microtubule polymerization , genetics , neuroscience , gene , dentate gyrus , hippocampal formation
Doublecortin X (DCX), a neuron‐specific microtubule‐associated protein, plays vital roles in microtubule organization and microtubule‐related developmental events. DCX directly binds to microtubules via its two evolutionarily conserved, structured doublecortin (DC) domains, N‐DC and C‐DC, and this interaction has been proposed to be regulated by flanking regions of the DCX N‐terminus and the C‐terminus. Although DCX is known to regulate microtubule function, its precise mechanism of action is yet to be determined. In our study, we are investigating the mechanism of cytoskeletal arrangement by DCX through identification of the impact of DCX pathogenic mutations within the N‐DC domain and DCX N‐terminus on microtubule network organization. A recently identified pathogenic mutation in the DCX N‐terminus, E2K (that resulted in epilepsy), and a mutant within the N‐DC domain, R102S (that resulted in X‐linked lissencephaly) have been studied to define the effects of these missense mutations on microtubule polymerization and bundling. Specifically, we are interested in defining if there are common features shared by these two mutants that may explain their pathological impacts. Our results so far have indicated that DCX wildtype and the DCX E2K mutant induce comparable levels of microtubule bundling while the DCX R102S mutant showed reduced bundling ability. Our studies on the pathogenic mutant DCX R102S showed its decreased microtubule bundling ability as well as its attenuated actions in microtubule polymerization of the cells. However, these results have not been observed for DCX E2K mutant. Ongoing studies will continue to explore shared actions of DCX E2K and R102S mutants, particularly their phospho‐dependent regulation. Taken together, these results emphasize the critical regulation of microtubule organization by DCX but the need for further investigations of the role of DCX and DCX pathogenic mutants in the modulation of microtubule organization to improve our understanding of the pathogenesis of neuronal migration disorders.