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

• 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
• Journal Title: Molecular Biology of the Cell
• Volume: Volume 27, Number 3
• Publisher: American Society for Cell Biology | 2016-02-01, Pages 518-534
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1091/mbc.E15-07-0504
• Subjects: Biology, Cell; Biology, Molecular; Chemistry, Biochemistry
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; RETARDATION PROTEIN INTERACTIONS; G-QUADRUPLEX; CIRCULAR-DICHROISM; NERVOUS-SYSTEM; HIPPOCAMPAL-NEURONS; REGULATORY ELEMENT; NEURITE OUTGROWTH; NMR-SPECTROSCOPY; BINDING-PROTEIN; GENE-EXPRESSION

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.