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Tao Yang PhD dissertation APA.pdf (9.54 MB)

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The role of miRNAs in Slit-mediated commissural axon guidance

Yang, Tao
http://orcid.org/0000-0002-1412-3824
http://rave.ohiolink.edu/etdc/view?acc_num=toledo154455366176285

Abstract Details

2018, Doctor of Philosophy, University of Toledo, Biology (Cell-Molecular Biology).
During brain development, neurons extend axons to reach their targets, a process called axon pathfinding or axon guidance. A variety of guidance cues have been identified in the developing nervous system such as Netrins, Semaphorins, Ephrins and Slits. In the developing spinal cord, the floor plate strongly expresses both Netrins and Slits, which collaborate with each other to attract pre-crossing and repel post-crossing commissural axons, respectively. Slit repulsion is silenced in pre-crossing commissural axons, which allows commissural axons to be attracted by Netrins and project toward the floor plate. However, the Slit repulsion is up-regulated and the Netrin attraction is inhibited in post-crossing axons, which prevents commissural axons from re-crossing the midline. Currently, the silencing mechanisms of attraction vs. repulsion are not fully understood. Previous studies suggested that regulation of protein levels of endogenous Robos, Slit receptors, plays an important role in these processes. Robo1 is expressed at extremely low levels in the growth cone of pre-crossing commissural axons. However, expression of Robo1 is dramatically up-regulated in commissural axons after the midline crossing. How is the expression of Robo1 regulated? Down-regulation of the target gene expression by microRNAs is crucial for neurogenesis, neuronal maturation and brain development. Our preliminary studies indicate that several microRNAs targeted the three prime untranslated region (3’UTR) of Robo1 are differentially expressed in the developing mouse dorsal spinal cord. Over-expression of these microRNAs into E13 mice spinal cord neurons suppressed expression of endogenous Robo1. Therefore, we hypothesize that microRNAs are able to regulate Robo1 expression and play an important role in spinal cord commissural axon projection. We found that the regulation of Robo1 gene expression is mediated by Robo1 3’UTR. miR-92, a highly conserved miRNA in multiple species, represses Robo1 expression in a miR-92-MRE dependent manner. Moreover, both in situ hybridization and immunohistochemistry in chicken embryos showed that gga-miR-92 and Robo1 have a differential expression pattern in the developing chicken spinal cord. miR-92 is highly expressed in precrossing commissural neurons, while Robo1 is strongly expressed in postcrossing commissural neurons. Furthermore, miR-92 can specifically repress Robo1 by translational repression rather than mRNA degradation and directly regulate Robo1 local translation in the growth cone. Additionally, results from in vitro explants co-culture assay suggested that miR-92 can control Slit2 sensitivities in Slit/Robo1-mediated commissural axon guidance and midline crossing by regulating Robo1 in a miR-92 MRE dependent manner. Finally, the interaction between Robo1 and miR-92 is required in commissural axon projections in vivo.
Guofa Liu (Committee Chair)
Bruce Bamber (Committee Member)
Scott Leisner (Committee Member)
Dragan Isailovic (Committee Member)
Joshua Park (Committee Member)
141 p.
Biology

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Citations

  • Yang, T. (2018). The role of miRNAs in Slit-mediated commissural axon guidance [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo154455366176285

    APA Style (7th edition)

  • Yang, Tao. The role of miRNAs in Slit-mediated commissural axon guidance. 2018. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo154455366176285.

    MLA Style (8th edition)

  • Yang, Tao. "The role of miRNAs in Slit-mediated commissural axon guidance." Doctoral dissertation, University of Toledo, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo154455366176285

    Chicago Manual of Style (17th edition)

toledo154455366176285
341
© 2018, some rights reserved.Creative Commons License The role of miRNAs in Slit-mediated commissural axon guidance by Tao Yang is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo and OhioLINK.