Cytoplasmic cleavage of IMPA1 3′ UTR is necessary for maintaining axon integrity
Catia Andreassi,
Raphaëlle Luisier,
Hamish Crerar,
Marousa Darsinou,
Sasja Blokzijl-Franke,
Tchern Lenn,
Nicholas M. Luscombe,
Giovanni Cuda,
Marco Gaspari,
Adolfo Saiardi,
Antonella Riccio
Affiliations
Catia Andreassi
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
Raphaëlle Luisier
Francis Crick Institute, London NW1 1AT, UK
Hamish Crerar
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
Marousa Darsinou
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
Sasja Blokzijl-Franke
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
Tchern Lenn
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
Nicholas M. Luscombe
Francis Crick Institute, London NW1 1AT, UK; UCL Genetics Institute, University College London, London WC1E 6BT, UK
Giovanni Cuda
Research Centre for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro 88100, Italy
Marco Gaspari
Research Centre for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro 88100, Italy
Adolfo Saiardi
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
Antonella Riccio
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Corresponding author
Summary: The 3′ untranslated regions (3′ UTRs) of messenger RNAs (mRNAs) are non-coding sequences involved in many aspects of mRNA metabolism, including intracellular localization and translation. Incorrect processing and delivery of mRNA cause severe developmental defects and have been implicated in many neurological disorders. Here, we use deep sequencing to show that in sympathetic neuron axons, the 3′ UTRs of many transcripts undergo cleavage, generating isoforms that express the coding sequence with a short 3′ UTR and stable 3′ UTR-derived fragments of unknown function. Cleavage of the long 3′ UTR of Inositol Monophosphatase 1 (IMPA1) mediated by a protein complex containing the endonuclease argonaute 2 (Ago2) generates a translatable isoform that is necessary for maintaining the integrity of sympathetic neuron axons. Thus, our study provides a mechanism of mRNA metabolism that simultaneously regulates local protein synthesis and generates an additional class of 3′ UTR-derived RNAs.
