Cytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr

Saeede Salehi, Abdolhossein Zare, Gianluca Prezza, Jakob Bader, Cornelius Schneider, Utz Fischer, Felix Meissner, Matthias Mann, Michael Briese () and Michael Sendtner ()
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Saeede Salehi: Institute of Clinical Neurobiology, University Hospital Wuerzburg
Abdolhossein Zare: Institute of Clinical Neurobiology, University Hospital Wuerzburg
Gianluca Prezza: Institute of Clinical Neurobiology, University Hospital Wuerzburg
Jakob Bader: Max Planck Institute of Biochemistry
Cornelius Schneider: Theodor Boveri Institute, University of Wuerzburg
Utz Fischer: Theodor Boveri Institute, University of Wuerzburg
Felix Meissner: Max Planck Institute of Biochemistry
Matthias Mann: Max Planck Institute of Biochemistry
Michael Briese: Institute of Clinical Neurobiology, University Hospital Wuerzburg
Michael Sendtner: Institute of Clinical Neurobiology, University Hospital Wuerzburg

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract The neuronal RNA-binding protein Ptbp2 regulates neuronal differentiation by modulating alternative splicing programs in the nucleus. Such programs contribute to axonogenesis by adjusting the levels of protein isoforms involved in axon growth and branching. While its functions in alternative splicing have been described in detail, cytosolic roles of Ptbp2 for axon growth have remained elusive. Here, we show that Ptbp2 is located in the cytosol including axons and growth cones of motoneurons, and that depletion of cytosolic Ptbp2 affects axon growth. We identify Ptbp2 as a major interactor of the 3’ UTR of Hnrnpr mRNA encoding the RNA-binding protein hnRNP R. Axonal localization of Hnrnpr mRNA and local synthesis of hnRNP R protein are strongly reduced when Ptbp2 is depleted, leading to defective axon growth. Ptbp2 regulates hnRNP R translation by mediating the association of Hnrnpr with ribosomes in a manner dependent on the translation factor eIF5A2. Our data thus suggest a mechanism whereby cytosolic Ptbp2 modulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein.

Date: 2023
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DOI: 10.1038/s41467-023-39787-6

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