Intra-axonal translation of Khsrp mRNA slows axon regeneration by destabilizing localized mRNAs
| Autor: | Patel, Priyanka, Buchanan, Courtney N, Zdradzinski, Matthew D, Sahoo, Pabitra K, Kar, Amar N, Lee, Seung Joon, Vaughn, Lauren S, Urisman, Anatoly, Oses-Prieto, Juan, Dell'Orco, Michela, Cassidy, Devon E, Costa, Irene Dalla, Miller, Sharmina, Thames, Elizabeth, Smith, Terika P, Burlingame, Alma L, Perrone-Bizzozero, Nora, Twiss, Jeffery L |
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| Rok vydání: | 2022 |
| Předmět: |
1.1 Normal biological development and functioning
Messenger Neurosciences RNA-Binding Proteins Neurodegenerative Biological Sciences Regenerative Medicine Sciatic Nerve Axons Rats Nerve Regeneration Mice Underpinning research Information and Computing Sciences Neurological Genetics Injury (total) Accidents/Adverse Effects Animals RNA Sprague-Dawley 3' Untranslated Regions Peripheral Neuropathy Environmental Sciences Biotechnology Developmental Biology |
| Zdroj: | Nucleic acids research, vol 50, iss 10 |
| Popis: | Axonally synthesized proteins support nerve regeneration through retrograde signaling and local growth mechanisms. RNA binding proteins (RBP) are needed for this and other aspects of post-transcriptional regulation of neuronal mRNAs, but only a limited number of axonal RBPs are known. We used targeted proteomics to profile RBPs in peripheral nerve axons. We detected 76 proteins with reported RNA binding activity in axoplasm, and levels of several change with axon injury and regeneration. RBPs with altered levels include KHSRP that decreases neurite outgrowth in developing CNS neurons. Axonal KHSRP levels rapidly increase after injury remaining elevated up to 28 days post axotomy. Khsrp mRNA localizes into axons and the rapid increase in axonal KHSRP is through local translation of Khsrp mRNA in axons. KHSRP can bind to mRNAs with 3'UTR AU-rich elements and targets those transcripts to the cytoplasmic exosome for degradation. KHSRP knockout mice show increased axonal levels of KHSRP target mRNAs, Gap43, Snap25, and Fubp1, following sciatic nerve injury and these mice show accelerated nerve regeneration in vivo. Together, our data indicate that axonal translation of the RNA binding protein Khsrp mRNA following nerve injury serves to promote decay of other axonal mRNAs and slow axon regeneration. |
| Databáze: | OpenAIRE |
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