title: Activation of Aurora-A is essential for neuronal migration via modulation of microtubule organization.
abstract: Neuronal migration is a critical feature to ensure proper location and wiring of neurons during cortical development. Postmitotic neurons migrate from the ventricular zone into the cortical plate to establish neuronal lamina in an "inside-out" gradient of maturation. Here, we report that the mitotic kinase Aurora-A is critical for the regulation of microtubule organization during neuronal migration via an Aurora-A-NDEL1 pathway in the mouse. Suppression of Aurora-A activity by inhibitors or siRNA resulted in severe impairment of neuronal migration of granular neurons. In addition, in utero injection of the Aurora-A kinase-dead mutant provoked defective migration of cortical neurons. Furthermore, we demonstrated that suppression of Aurora-A impaired microtubule modulation in migrating neurons. Interestingly, suppression of CDK5 by an inhibitor or siRNA reduced Aurora-A activity and NDEL1 phosphorylation by Aurora-A, which led to defective neuronal migration. We found that CDK5RAP2 is a key molecule that mediates functional interaction and is essential for centrosomal targeting of Aurora-A. Our observations demonstrated novel and surprising cross talk between Aurora-A and CDK5 during neuronal migration.
authors.affiliation: Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Takitoh
authors.forename: Kanako
authors.initials: K
authors.lastname: Kumamoto
authors.forename: Chen-Chi
authors.initials: CC
authors.lastname: Wang
authors.forename: Makoto
authors.initials: M
authors.lastname: Sato
authors.forename: Shiori
authors.initials: S
authors.lastname: Toba
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
mesh_terms: D000638:Amiodarone; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077546:Roscovitine; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000638:Amiodarone; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001973:Bromodeoxyuridine; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D051360:Cyclin-Dependent Kinase 5; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011687:Purines; D034741:RNA, Small Interfering; D000077546:Roscovitine; C549613:Cdk5rap2 protein, mouse; C424436:Cetn2 protein, mouse; C522423:EB3 protein, mouse; C486015:Ndel1 protein, mouse; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576918:Aurka protein, mouse