Repeat-element RNAs integrate a neuronal growth circuit

Eitan Erez Zahavi; Indrek Koppel; Riki Kawaguchi; Juan A Oses-Prieto; Adam Briner; Aboozar Monavarfeshani; Irene Dalla Costa; Erna van Niekerk; Jinyoung Lee; Samaneh Matoo; Shane Hegarty; Ryan J Donahue; Pabitra K Sahoo; Shifra Ben-Dor; Ester Feldmesser; Julia Ryvkin; Dena Leshkowitz; Rotem Ben-Tov Perry; Yuyan Cheng; Eli Farber; Ofri Abraham; Nitzan Samra; Nataliya Okladnikov; Stefanie Alber; Christin A Albus; Ida Rishal; Igor Ulitsky; Mark H Tuszynski; Jeffery L Twiss; Zhigang He; Alma L Burlingame; Mike Fainzilber

doi:10.1016/j.cell.2025.04.030

Repeat-element RNAs integrate a neuronal growth circuit

Cell. 2025 May 12:S0092-8674(25)00498-2. doi: 10.1016/j.cell.2025.04.030. Online ahead of print.

Authors

Eitan Erez Zahavi¹, Indrek Koppel², Riki Kawaguchi³, Juan A Oses-Prieto⁴, Adam Briner¹, Aboozar Monavarfeshani⁵, Irene Dalla Costa⁶, Erna van Niekerk⁷, Jinyoung Lee⁶, Samaneh Matoo⁶, Shane Hegarty⁵, Ryan J Donahue⁵, Pabitra K Sahoo⁸, Shifra Ben-Dor⁹, Ester Feldmesser⁹, Julia Ryvkin⁹, Dena Leshkowitz⁹, Rotem Ben-Tov Perry¹⁰, Yuyan Cheng¹¹, Eli Farber¹, Ofri Abraham¹, Nitzan Samra¹, Nataliya Okladnikov¹, Stefanie Alber¹, Christin A Albus¹², Ida Rishal¹, Igor Ulitsky¹⁰, Mark H Tuszynski⁷, Jeffery L Twiss⁶, Zhigang He⁵, Alma L Burlingame⁴, Mike Fainzilber¹³

Affiliations

¹ Departments of Biomolecular Sciences and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.
² Departments of Biomolecular Sciences and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel; Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia. Electronic address: indrek.koppel@taltech.ee.
³ Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
⁴ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
⁷ Department of Neurosciences, University of California, San Diego, and Veterans Administration Medical Center, San Diego, CA 92093, USA.
⁸ Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA; Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
⁹ Bioinformatics Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
¹⁰ Departments of Immunology and Regenerative Biology and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.
¹¹ Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹² Departments of Biomolecular Sciences and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel; Newcastle University Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK.
¹³ Departments of Biomolecular Sciences and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel. Electronic address: mike.fainzilber@weizmann.ac.il.

PMID: 40381624
DOI: 10.1016/j.cell.2025.04.030

Abstract

Neuronal growth and regeneration are regulated by local translation of mRNAs in axons. We examined RNA polyadenylation changes upon sensory neuron injury and found upregulation of a subset of polyadenylated B2-SINE repeat elements, hereby termed GI-SINEs (growth-inducing B2-SINEs). GI-SINEs are induced from ATF3 and other AP-1 promoter-associated extragenic loci in injured sensory neurons but are not upregulated in lesioned retinal ganglion neurons. Exogenous GI-SINE expression elicited axonal growth in injured sensory, retinal, and corticospinal tract neurons. GI-SINEs interact with ribosomal proteins and nucleolin, an axon-growth-regulating RNA-binding protein, to regulate translation in neuronal cytoplasm. Finally, antisense oligos against GI-SINEs perturb sensory neuron outgrowth and nucleolin-ribosome interactions. Thus, a specific subfamily of transposable elements is integral to a physiological circuit linking AP-1 transcription with localized RNA translation.

Keywords: RNA localization; Short Interspersed Nuclear Elements; axon growth; axonal transport; local translation; nerve injury; neuronal length sensing; non-coding RNA.