hnRNP-Q1 represses nascent axon growth in cortical neurons by inhibiting Gap-43 mRNA translation

• Type of Material: Article
• Authors: Kathryn R. Williams, Emory University; Damian S. McAninch, Duquesne University; Snezana Stefanovic, Duquesne University; Lei Xing, Emory University; Megan Allen, Emory University; Wenqi Li, Emory University; Yue Feng, Emory University; Mihaela Rita Mihailescu, Duquesne University; Gary Bassell, Emory University
• Language: English
• Date: 2016-02-01
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Williams et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E15-07-0504
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 27
• Issue: 3
• Start Page: 518
• End Page: 534
• Grant/Funding Information: This project was supported by a Muscular Dystrophy Association Grant (G.J.B.) and National Institutes of Health training grants (T32GM008367-21, 5T32GM008367-22) and an Individual Predoctoral Ruth L. Kirschstein National Research Service Award 1F31MH095266-01A1 (K.R.W.).
• Keywords: Life Sciences & Biomedicine; CIRCULAR-DICHROISM; GENE-EXPRESSION; REGULATORY ELEMENT; Cell Biology; BINDING-PROTEIN; HIPPOCAMPAL-NEURONS; G-QUADRUPLEX; RETARDATION PROTEIN INTERACTIONS; Science & Technology; NMR-SPECTROSCOPY; NEURITE OUTGROWTH; NERVOUS-SYSTEM
• Research Categories: Chemistry, Biochemistry; Biology, Molecular; Biology, Cell

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.