title: Doublecortin (Dcx) family proteins regulate filamentous actin structure in developing neurons.
abstract: Doublecortin (Dcx) is the causative gene for X-linked lissencephaly, which encodes a microtubule-binding protein. Axon tracts are abnormal in both affected individuals and in animal models. To determine the reason for the axon tract defect, we performed a semiquantitative proteomic analysis of the corpus callosum in mice mutant for Dcx. In axons from mice mutant for Dcx, widespread differences are found in actin-associated proteins as compared with wild-type axons. Decreases in actin-binding proteins α-actinin-1 and α-actinin-4 and actin-related protein 2/3 complex subunit 3 (Arp3), are correlated with dysregulation in the distribution of filamentous actin (F-actin) in the mutant neurons with increased F-actin around the cell body and decreased F-actin in the neurites and growth cones. The actin distribution defect can be rescued by full-length Dcx and further enhanced by Dcx S297A, the unphosphorylatable mutant, but not with the truncation mutant of Dcx missing the C-terminal S/P-rich domain. Thus, the C-terminal region of Dcx dynamically regulates formation of F-actin features in developing neurons, likely through interaction with spinophilin, but not through α-actinin-4 or Arp3. We show with that the phenotype of Dcx/Doublecortin-like kinase 1 deficiency is consistent with actin defect, as these axons are selectively deficient in axon guidance, but not elongation.
authors.affiliation: Center for Neuroscience Research and Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Fu
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Brown
authors.forename: Chan Choo
authors.initials: CC
authors.lastname: Yap
authors.forename: Bettina
authors.initials: B
authors.lastname: Winckler
authors.forename: Jyoti K
authors.initials: JK
authors.lastname: Jaiswal
authors.forename: Judy S
authors.initials: JS
authors.lastname: Liu
mesh_terms: D051378:Actin-Related Protein 3 / Q000378:metabolism; D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D016208:Databases, Factual; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D040901:Proteomics; D000099273:Neurabins
chemical_list: D051378:Actin-Related Protein 3; D000185:Actinin; D000199:Actins; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009479:Neuropeptides; D000099273:Neurabins; C491752:Actn4 protein, mouse; C000714847:Dcx protein, mouse