title: Synergistic nuclear import of NeuroD1 and its partner transcription factor, E47, via heterodimerization.
abstract: The transition from undifferentiated pluripotent cells to terminally differentiated neurons is coordinated by a repertoire of transcription factors. NeuroD1 is a type II basic helix loop helix (bHLH) transcription factor that plays critical roles in neuronal differentiation and maintenance in the central nervous system. Its dimerization with E47, a type I bHLH transcription factor, leads to the transcriptional regulation of target genes. Mounting evidence suggests that regulating the localization of transcription factors contributes to the regulation of their activity during development as defects in their localization underlie a variety of developmental disorders. In this study, we attempted to understand the nuclear import mannerisms of NeuroD1 and E47. We found that the nuclear import of NeuroD1 and E47 is energy-dependent and involves the Ran-mediated pathway. Herein, we demonstrate that NeuroD1 and E47 can dimerize inside the cytoplasm before their nuclear import. Moreover, this dimerization promotes nuclear import as the nuclear accumulation of NeuroD1 was enhanced in the presence of E47 in an in vitro nuclear import assay, and NLS-deficient NeuroD1 was successfully imported into the nucleus upon E47 overexpression. NeuroD1 also had a similar effect on the nuclear accumulation of NLS-deficient E47. These findings suggest a novel role for dimerization that may promote, at least partially, the nuclear import of transcription factors allowing them to function efficiently in the nucleus.
authors.affiliation: Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Rashid
authors.initials: R
authors.lastname: Mehmood
authors.forename: Noriko
authors.initials: N
authors.lastname: Yasuhara
authors.forename: Souichi
authors.initials: S
authors.lastname: Oe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoneda
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D024361:Amino Acids, Basic / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D019913:Nuclear Localization Signals; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051381:Rats; D051820:TCF Transcription Factors / Q000378:metabolism*; D013816:Thermodynamics; D058125:Transcription Factor 7-Like 1 Protein; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D024361:Amino Acids, Basic; D051792:Basic Helix-Loop-Helix Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D020931:ran GTP-Binding Protein; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; C093564:Neurogenic differentiation factor 1