دورية أكاديمية
An Image-Based miRNA Screen Identifies miRNA-135s As Regulators of CNS Axon Growth and Regeneration by Targeting Krüppel-like Factor 4.
| العنوان: | An Image-Based miRNA Screen Identifies miRNA-135s As Regulators of CNS Axon Growth and Regeneration by Targeting Krüppel-like Factor 4. |
|---|---|
| المؤلفون: | van Battum EY; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands., Verhagen MG; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands., Vangoor VR; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands., Fujita Y; Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan., Derijck AAHA; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands., O'Duibhir E; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands., Giuliani G; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands., de Gunst T; InteRNA Technologies B.V., Yalelaan 62, 3584 CM Utrecht, The Netherlands, and., Adolfs Y; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands., Lelieveld D; Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Egan D; Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Schaapveld RQJ; InteRNA Technologies B.V., Yalelaan 62, 3584 CM Utrecht, The Netherlands, and., Yamashita T; Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan., Pasterkamp RJ; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands, r.j.pasterkamp@umcutrecht.nl. |
| المصدر: | The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2018 Jan 17; Vol. 38 (3), pp. 613-630. Date of Electronic Publication: 2017 Dec 01. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington, DC : Society for Neuroscience Original Publication: [Baltimore, Md.] : The Society, c1981- |
| مواضيع طبية MeSH: | Gene Expression Regulation/*physiology , Kruppel-Like Transcription Factors/*metabolism , MicroRNAs/*metabolism , Nerve Regeneration/*physiology, Animals ; Axons/metabolism ; Female ; Humans ; Kruppel-Like Factor 4 ; Male ; Mice ; Mice, Inbred C57BL ; Retinal Ganglion Cells/physiology |
| مستخلص: | During embryonic development, axons extend over long distances to establish functional connections. In contrast, axon regeneration in the adult mammalian CNS is limited in part by a reduced intrinsic capacity for axon growth. Therefore, insight into the intrinsic control of axon growth may provide new avenues for enhancing CNS regeneration. Here, we performed one of the first miRNome-wide functional miRNA screens to identify miRNAs with robust effects on axon growth. High-content screening identified miR-135a and miR-135b as potent stimulators of axon growth and cortical neuron migration in vitro and in vivo in male and female mice. Intriguingly, both of these developmental effects of miR-135s relied in part on silencing of Krüppel-like factor 4 (KLF4), a well known intrinsic inhibitor of axon growth and regeneration. These results prompted us to test the effect of miR-135s on axon regeneration after injury. Our results show that intravitreal application of miR-135s facilitates retinal ganglion cell (RGC) axon regeneration after optic nerve injury in adult mice in part by repressing KLF4. In contrast, depletion of miR-135s further reduced RGC axon regeneration. Together, these data identify a novel neuronal role for miR-135s and the miR-135-KLF4 pathway and highlight the potential of miRNAs as tools for enhancing CNS axon regeneration. SIGNIFICANCE STATEMENT Axon regeneration in the adult mammalian CNS is limited in part by a reduced intrinsic capacity for axon growth. Therefore, insight into the intrinsic control of axon growth may provide new avenues for enhancing regeneration. By performing an miRNome-wide functional screen, our studies identify miR-135s as stimulators of axon growth and neuron migration and show that intravitreal application of these miRNAs facilitates CNS axon regeneration after nerve injury in adult mice. Intriguingly, these developmental and regeneration-promoting effects rely in part on silencing of Krüppel-like factor 4 (KLF4), a well known intrinsic inhibitor of axon regeneration. Our data identify a novel neuronal role for the miR-135-KLF4 pathway and support the idea that miRNAs can be used for enhancing CNS axon regeneration. (Copyright © 2018 the authors 0270-6474/18/380614-18$15.00/0.) |
| References: | Science. 2001 Oct 26;294(5543):853-8. (PMID: 11679670) Curr Biol. 2002 Apr 30;12(9):735-9. (PMID: 12007417) Genome Biol. 2004;5(3):R13. (PMID: 15003116) Cancer Res. 2008 Jul 15;68(14):5795-802. (PMID: 18632633) Nucleic Acids Res. 2009 Jan;37(Database issue):D105-10. (PMID: 18996891) Science. 2009 Oct 9;326(5950):298-301. (PMID: 19815778) Mol Cell Neurosci. 2010 May;44(1):43-54. (PMID: 20159039) BMC Genomics. 2011 Nov 03;12:546. (PMID: 22050702) Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21117-21. (PMID: 22160720) Exp Neurol. 2012 Jan;233(1):555-65. (PMID: 22178326) Nat Neurosci. 2012 Mar 11;15(5):703-12. (PMID: 22406547) Cell Mol Life Sci. 2012 Sep;69(18):3127-45. (PMID: 22535415) Genes Dev. 2012 Jul 15;26(14):1612-25. (PMID: 22759636) Mol Cell Biol. 2012 Nov;32(21):4297-305. (PMID: 22907754) Semin Cell Dev Biol. 2013 Mar;24(3):146-55. (PMID: 23219835) J Neurophysiol. 2013 Apr;109(7):1979-88. (PMID: 23343890) Science. 2013 Apr 19;340(6130):372-376. (PMID: 23599497) Nat Commun. 2013;4:1877. (PMID: 23695671) Mol Psychiatry. 2014 Jul;19(7):848-52. (PMID: 23917947) Nat Commun. 2013;4:2633. (PMID: 24129709) Front Oncol. 2013 Oct 22;3:268. (PMID: 24156094) Eur J Hum Genet. 2014 Jun;22(6):840-3. (PMID: 24169524) J Urol. 2014 Apr;191(4):1174-80. (PMID: 24184258) J Neurosci. 2014 Jan 1;34(1):66-78. (PMID: 24381269) Nat Commun. 2014;5:3263. (PMID: 24535612) Clin Cancer Res. 2014 Jun 1;20(11):2994-3002. (PMID: 24691020) Cancer Cell. 2014 Apr 14;25(4):469-83. (PMID: 24735923) Invest Ophthalmol Vis Sci. 2014 Jun 06;55(7):4369-77. (PMID: 24906860) Neuron. 2014 Jun 4;82(5):1058-73. (PMID: 24908486) Neuron. 2014 Jul 16;83(2):344-360. (PMID: 24952960) Nat Commun. 2014 Jul 10;5:4317. (PMID: 25007825) Philos Trans R Soc Lond B Biol Sci. 2014 Sep 26;369(1652):null. (PMID: 25135976) Neural Regen Res. 2014 Aug 1;9(15):1418-21. (PMID: 25317150) CNS Neurol Disord Drug Targets. 2015;14(8):1096-102. (PMID: 25801837) Front Mol Neurosci. 2015 Jun 11;8:23. (PMID: 26113809) Int J Mol Med. 2015 Sep;36(3):669-77. (PMID: 26134897) Curr Vasc Pharmacol. 2016;14(2):211-8. (PMID: 26202084) Biochem Biophys Res Commun. 2015 Sep 11;465(1):125-30. (PMID: 26235874) Int J Clin Exp Pathol. 2015 Jun 01;8(6):6356-66. (PMID: 26261511) Cell Death Dis. 2015 Aug 27;6:e1865. (PMID: 26313916) PLoS One. 2015 Sep 02;10(9):e0137461. (PMID: 26331719) Dev Cell. 2015 Dec 7;35(5):537-552. (PMID: 26651291) eNeuro. 2016 Feb 27;3(1):null. (PMID: 27022622) Neural Dev. 2016 Apr 05;11:9. (PMID: 27048518) Neurosci Lett. 2016 May 27;622:61-6. (PMID: 27102143) Neuron. 2016 May 4;90(3):437-51. (PMID: 27151637) Oncotarget. 2016 Jul 5;7(27):42566-42578. (PMID: 27302923) J Neurosci. 2016 Aug 10;36(32):8516-32. (PMID: 27511021) Genet Mol Res. 2016 Aug 12;15(3):. (PMID: 27525941) Neural Plast. 2016;2016:1279051. (PMID: 27818801) Front Surg. 2016 Nov 08;3:56. (PMID: 27878119) |
| فهرسة مساهمة: | Keywords: KLF4; axon growth; intrinsic; microRNA; regeneration |
| المشرفين على المادة: | 0 (KLF4 protein, human) 0 (Klf4 protein, mouse) 0 (Kruppel-Like Factor 4) 0 (Kruppel-Like Transcription Factors) 0 (MIRN135 microRNA, human) 0 (MicroRNAs) 0 (Mirn135 microRNA, mouse) |
| تواريخ الأحداث: | Date Created: 20171203 Date Completed: 20190228 Latest Revision: 20211204 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6596187 |
| DOI: | 10.1523/JNEUROSCI.0662-17.2017 |
| PMID: | 29196317 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1529-2401 |
|---|---|
| DOI: | 10.1523/JNEUROSCI.0662-17.2017 |