title: Proper Level of Cytosolic Disabled-1, Which Is Regulated by Dual Nuclear Translocation Pathways, Is Important for Cortical Neuronal Migration.
abstract: Disabled-1 (Dab1) is an essential intracellular protein in the Reelin pathway. It has a nuclear localization signal (NLS; hereafter referred to as "NLS1") and 2 nuclear export signals, and shuttles between the nucleus and the cytoplasm. In this study, we found that Dab1 has an additional unidentified NLS, and that the Dab1 NLS1 mutant could translocate to the nucleus in an unconventional ATP/temperature-dependent and cytoplasmic factor/RanGTP gradient-independent manner. Additional mutations in the NLS1 mutant revealed that K(67) and K(69) are important for the nuclear transport. Furthermore, an excess of the intracellular domain of the Reelin receptors inhibited the nuclear translocation of Dab1. An in utero electroporation study showed that a large amount of Dab1 in the cytoplasm in migrating neurons inhibited the migration, and that forced transport of Dab1 into the nucleus attenuated this inhibitory effect. In addition, rescue experiments using yotari, an autosomal recessive mutant of dab1, revealed that cells expressing Dab1 NLS1 mutant tend to distribute at more superficial positions than those expressing wild-type Dab1. Taken together, these findings suggest that Dab1 has at least 2 NLSs, and that the regulation of the subcellular localization of Dab1 is important for the proper migration of excitatory neurons.
authors.affiliation: Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakajima
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D000091042:Reelin Protein; D013696:Temperature; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: C103773:Dab1 protein, mouse; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; C102460:Ran protein, mouse; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D051880:Receptors, Notch; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C469363:reelin receptor; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D020931:ran GTP-Binding Protein
keywords: Dab1; nuclear localization signal; reeler; reelin; yotari