Importin alpha 3 governs the crosstalk between extrinsic and intrinsic signals in peripheral nerve regeneration.
Sensory neurons have the capacity to grow long distances and high morphological plasticity during development. Upon injury this plasticity is reactivated and causes neuropathic pain due to axonal misguidance and excessive branching. Axonal outgrowth upon injury is regulated by the importin alpha 3 (IMPa3). To understand how neuronal growth causes pain, we study IMPa3’s role in the retrograde signaling. Extrinsic factors such as neurotrophins are released at the injury site of the sciatic nerve and elicit retrograde signalling that is carried by IMPa3 back into the nucleus, where it initiates regeneration-specific transcription. Our in vitro data shows that loss of IMPa3 has severe consequences on neuronal morphology such as impaired neuronal outgrowth. Our in vivo post-injury RNAseq data shows a clear regeneration-specific signature, yielding many functionally interesting candidate genes downstream of IMPa3. Using an in vitro model for axotomy, we now validate these genes, demonstrating that down-regulation of COMP, an extracellular matrix protein, can rescue neurite-outgrowth deficiency in IMPa3 deficient neurons. We are aiming to identify the regeneration-specific transcription factors that drive the expression of our validated candidate genes such as COMP. These transcription factors are putative regulators of regeneration and can thus be used in a therapeutic approach to promote regeneration in the peripheral nervous system and suppress neuropathic pain.
Selected publications:
- S Alber, P Di Matteo, MD Zdradzinski, I Dalla Costa, KF Medzihradszky, R Kawaguchi, A Di Pizio, P Freund, N Panayotis, L Marvaldi, E Doron-Mandel, N Okladnikov, I Rishal, R Nevo, G Coppola, SJ Lee, PK Sahoo, AL Burlingame, JL Twiss, M Fainzilber. PTBP1 regulates injury responses and sensory pathways in adult peripheral neurons. Sci Adv. 2023 Jul 28;9(30):eadi0286. doi: 10.1126/sciadv.adi0286. Epub 2023 Jul 28.
- N. Panayotis, P. Freund, L. Marvaldi, T. Shalit, A. Brandis, T Mehlman, M. Tsoory, M. Fainzilber. β-Sitosterol Reduces Anxiety and Synergizes with Established Anxiolytic Drugs in mice. Cell Reports Medicine doi: 10.1016/j.xcrm.2021.100281 (2021).
- L. Marvaldi, N. Panayotis, S. Alber°, S.-Y. Dagan°, N. Okladinikov, I. Koppel, A. Di Pizio, D.-A. Song, Y. Tzur, M. Terenzio, I. Rishal, D. Gordon, F. Rother, E. Hartmann, M. Bader, and M. Fainzilber. Importin α3 regulates chronic pain pathways in peripheral sensory neurons. Science 369, (6505):842-846 (2020). This work has been highlighted in a perspective piece in Science 369, (6505) 774-775 (2020) and in Nature Chemical Biology 1037 (2020) and recommended by Ji R: Faculty Opinions Recommendation 22 Sep 2020; 10.3410/f.738498141.793578282.
- B.-C. Tamin-Yecheskel°, M. Fraiberg°, K. Kokabi°, S. Freud, O. Shatz, L. Marvaldi, N. Subic, O. Brenner, M. Tsoory, R. Eilam-Altstadter, I. Biton, A. Savidor, G. Heimer, C. Behrendes, B Ben-Zeev, Z. Elazar. Novel mouse model simulating spastic paraplegia type 49 reveals defects in autophagosomal consumption. Autophagy 10.1080/15548627.2020.1852724 (2020).
- M. Terenzio, S. Koley, N. Samra, I. Rishal, Q. Zhao, P. K. Sahoo, A. Urisman, L. Marvaldi, J. A. Oses-Prieto, C. Forester, C. Gomes, A. L. Kalinski, A. Di Pizio, E. Doron-Mandel, R. B.-T. Perry, I. Koppel, J. L. Twiss, A. L. Burlingame, M. Fainzilber, Locally translated mTOR controls axonal local translation in nerve injury. Science. 359, 1416–1421 (2018).
- L. Marvaldi, S. Thongrong, A. Kozłowska, R. Irschick, C. O. Pritz, B. Bäumer, G. Ronchi, S. Geuna, B. Hausott, L. Klimaschewski, Enhanced axon outgrowth and improved long-distance axon regeneration in sprouty2 deficient mice. Dev. Neurobiol. 75, 217–231 (2015).