title: hnRNP-Q1 represses nascent axon growth in cortical neurons by inhibiting Gap-43 mRNA translation.
abstract: Posttranscriptional regulation of gene expression by mRNA-binding proteins is critical for neuronal development and function. hnRNP-Q1 is an mRNA-binding protein that regulates mRNA processing events, including translational repression. hnRNP-Q1 is highly expressed in brain tissue, suggesting a function in regulating genes critical for neuronal development. In this study, we have identified Growth-associated protein 43 (Gap-43) mRNA as a novel target of hnRNP-Q1 and have demonstrated that hnRNP-Q1 represses Gap-43 mRNA translation and consequently GAP-43 function. GAP-43 is a neuronal protein that regulates actin dynamics in growth cones and facilitates axonal growth. Previous studies have identified factors that regulate Gap-43 mRNA stability and localization, but it remains unclear whether Gap-43 mRNA translation is also regulated. Our results reveal that hnRNP-Q1 knockdown increased nascent axon length, total neurite length, and neurite number in mouse embryonic cortical neurons and enhanced Neuro2a cell process extension; these phenotypes were rescued by GAP-43 knockdown. Additionally, we have identified a G-quadruplex structure in the 5' untranslated region of Gap-43 mRNA that directly interacts with hnRNP-Q1 as a means to inhibit Gap-43 mRNA translation. Therefore hnRNP-Q1-mediated repression of Gap-43 mRNA translation provides an additional mechanism for regulating GAP-43 expression and function and may be critical for neuronal development.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Williams
authors.affiliation: Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282.
authors.forename: Damian S
authors.initials: DS
authors.lastname: McAninch
authors.affiliation: Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282.
authors.forename: Snezana
authors.initials: S
authors.lastname: Stefanovic
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Lei
authors.initials: L
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Megan
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282.
authors.forename: Mihaela Rita
authors.initials: MR
authors.lastname: Mihailescu
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322 gbassel@emory.edu.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D049108:Cell Enlargement; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology; D054856:G-Quadruplexes; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D020439:Growth Cones / Q000502:physiology*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000502:physiology*; D051379:Mice; D016501:Neurites / Q000502:physiology; D061251:Primary Cell Culture; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D019922:GAP-43 Protein; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012333:RNA, Messenger; C486049:Syncrip protein, mouse