PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS
Abstract Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3‐kinase (PI3K)...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911674 |
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| author | Bart Nieuwenhuis Amanda C Barber Rachel S Evans Craig S Pearson Joachim Fuchs Amy R MacQueen Susan van Erp Barbara Haenzi Lianne A Hulshof Andrew Osborne Raquel Conceicao Tasneem Z Khatib Sarita S Deshpande Joshua Cave Charles Ffrench‐Constant Patrice D Smith Klaus Okkenhaug Britta J Eickholt Keith R Martin James W Fawcett Richard Eva |
| author_facet | Bart Nieuwenhuis Amanda C Barber Rachel S Evans Craig S Pearson Joachim Fuchs Amy R MacQueen Susan van Erp Barbara Haenzi Lianne A Hulshof Andrew Osborne Raquel Conceicao Tasneem Z Khatib Sarita S Deshpande Joshua Cave Charles Ffrench‐Constant Patrice D Smith Klaus Okkenhaug Britta J Eickholt Keith R Martin James W Fawcett Richard Eva |
| author_sort | Bart Nieuwenhuis |
| collection | DOAJ |
| description | Abstract Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3‐kinase (PI3K) and its product phosphatidylinositol (3,4,5)‐trisphosphate (PIP3). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion. |
| format | Article |
| id | doaj-art-774319b15576431a80d815b1901eaee3 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-774319b15576431a80d815b1901eaee32025-08-20T03:46:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-06-0112812410.15252/emmm.201911674PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNSBart Nieuwenhuis0Amanda C Barber1Rachel S Evans2Craig S Pearson3Joachim Fuchs4Amy R MacQueen5Susan van Erp6Barbara Haenzi7Lianne A Hulshof8Andrew Osborne9Raquel Conceicao10Tasneem Z Khatib11Sarita S Deshpande12Joshua Cave13Charles Ffrench‐Constant14Patrice D Smith15Klaus Okkenhaug16Britta J Eickholt17Keith R Martin18James W Fawcett19Richard Eva20John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeInstitute of Biochemistry, Charité – Universitätsmedizin BerlinLaboratory of Lymphocyte Signalling and Development, Babraham InstituteMRC Centre for Regenerative Medicine, University of EdinburghJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeMRC Centre for Regenerative Medicine, University of EdinburghDepartment of Neuroscience, Carleton UniversityDepartment of Pathology, University of CambridgeInstitute of Biochemistry, Charité – Universitätsmedizin BerlinJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeJohn Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of CambridgeAbstract Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3‐kinase (PI3K) and its product phosphatidylinositol (3,4,5)‐trisphosphate (PIP3). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.https://doi.org/10.15252/emmm.201911674axon transportCNS axon regenerationoptic nervep110 deltaphosphoinositide 3‐kinase |
| spellingShingle | Bart Nieuwenhuis Amanda C Barber Rachel S Evans Craig S Pearson Joachim Fuchs Amy R MacQueen Susan van Erp Barbara Haenzi Lianne A Hulshof Andrew Osborne Raquel Conceicao Tasneem Z Khatib Sarita S Deshpande Joshua Cave Charles Ffrench‐Constant Patrice D Smith Klaus Okkenhaug Britta J Eickholt Keith R Martin James W Fawcett Richard Eva PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS EMBO Molecular Medicine axon transport CNS axon regeneration optic nerve p110 delta phosphoinositide 3‐kinase |
| title | PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS |
| title_full | PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS |
| title_fullStr | PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS |
| title_full_unstemmed | PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS |
| title_short | PI 3‐kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS |
| title_sort | pi 3 kinase delta enhances axonal pip3 to support axon regeneration in the adult cns |
| topic | axon transport CNS axon regeneration optic nerve p110 delta phosphoinositide 3‐kinase |
| url | https://doi.org/10.15252/emmm.201911674 |
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