Volume 8, Issue 2, June 2020, Page: 38-44
Manifestation of Functional Defects of Nervous System in Upf3 Mutants Drosophila melanogaster at Larval and Adult Stages
Sanusi Ahmed Jega, Faculty of Biomedical Science, Kampala International University, Ishaka-Bushenyi, Uganda; Department of Biochemistry, Faculty of Life Sciences, Kebbi State University of Science and Technology, Aliero, Nigeria
Ahmed Adebowole Adedeji, Faculty of Biomedical Science, Kampala International University, Ishaka-Bushenyi, Uganda; Foresight Institute of Research and Translation, Ibadan, Nigeria
Marta Vicente-Crespo, Institute of Biomedical Research, Kampala International University, Ishaka-Bushenyi, Uganda; African Population and Health Research Center, Nairobi, Kenya
Received: Mar. 30, 2020;       Accepted: Apr. 13, 2020;       Published: May 14, 2020
DOI: 10.11648/j.ab.20200802.12      View  21      Downloads  19
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that cleans the system from possible harmful proteins and also regulates up to 10% of normal RNAs. The essential player proteins in the NMD (core NMD factors) are Upf1, Upf2, and Upf3. Mutation of any of these NMD factors cause ranges of effects in the development of various organisms. In humans, mutation of Upf3 was associated with neurodegenerative disorders, which include: attention deficit, schizophrenia autism, and intellectual disability. Using functional genetics approach and behavioral analysis methods we examined the loss of function effects of Upf3, in the nervous system function of a Drosophila melanogaster. We observed certain nervous system functional defects in homozygous Upf3 mutants. The embryos exhibited reduced and delayed hatching, the larvae manifested defects in motor function and the adults showed reduced climbing ability, defective short term memory, and learning, and notably, the adult life span was also reduced. This work has further revealed the prospect of Upf3 as a player gene for consideration in the management of neurodegenerative diseases. We explored this using Drosophila melanogaster as a model organism to mimic and study the neurodegenerative traits observed in the patients suffering from Upf3 mutation. Likewise, it suggests a further investigation into the mechanistic insight for the roles of Upf3 in both early and late CNS development.
Nonsense-mediated mRNA Decay, NMD Factors, Organismal Development, Neurodegenerative Behaviors, Drosophila melanogaster
To cite this article
Sanusi Ahmed Jega, Ahmed Adebowole Adedeji, Marta Vicente-Crespo, Manifestation of Functional Defects of Nervous System in Upf3 Mutants Drosophila melanogaster at Larval and Adult Stages, Advances in Biochemistry. Vol. 8, No. 2, 2020, pp. 38-44. doi: 10.11648/j.ab.20200802.12
Copyright © 2020 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Dyle, M. C., Kolakada, D., Cortazar, M. A. and Jagannathan, S. (2020). How to get away with nonsense: Mechanisms and consequences of escape from nonsense-mediated RNA decay. Wiley Interdiscip. Rev. RNA 11, 1–16.
Huang, L, Shum, E. Y., Jones, S. H., Lou, C.-H., Dumdie, J., Kim, H., Roberts, A. J., Jolly, L. A., Espinoza, J. L., Skarbrevik, D. M., Phan, M. H., Cook-Andersen, H., Swerdlow, N. R., Gecz, J., and Wilkinson, M. F. (2017). A Upf3b-mutant mouse model with behavioral and neurogenesis defects. Mol Psychiatry. 2018 Aug; 23 (8): 1773-1786.
Popp, M. W. and Maquat, L. E. (2016). Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine. Cell 165, 1319–1332.
Isken, O. and L. E. Maquat. The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nat Rev Genet 9, 699–712 (2008).
Wittkopp N., Huntzinger E., Weiler C., Saulière J., S. S., and Sonawane M., and Izaurralde E. (2009). Nonsense-mediated mRNA decay effectors are essential for zebrafish emryonic development. Mol Cell Biol. 2009 Jul; 29 (13): 3517-28.
Giannandrea, M., Guarnieri, F. C., Gehring, N. H., Monzani, E., Benfenati, F., Kulozik, A. E., and Valtorta, F. (2013). Nonsense-Mediated mRNA Decay and Loss-of-Function of the Protein Underlie the X-Linked Epilepsy Associated with the W3566 Mutation in Synapsin I. PLOS ONE, 8 (6), e67724.
Metzstein, M. M., and Krasnow, M. A. (2006). Functions of the Nonsense-Mediated mRNA Decay Pathway in Drosophila Development. PLoS GENETICS, 2 (12), e180.
Lou, C., Shum, E. Y. and Wilkinson, M. F. (2015). RNA degradation drives stem cell differentiation. EMBO J. 34, 2013–2015.
Alrahbeni, T., Sartor, F., Anderson, J., Miedzybrodzka, Z., McCaig, C., and Müller, B. (2015). Full UPF3B function is critical for neuronal differentiation of neural stem cells. Mol Brain. May 27; 8: 33.
Nickless, A., Cheruiyot, A., Flanagan, K. C., Piwnica-Worms, D., Stewart, S. A., and You, Z. (2017). p38 MAPK inhibits nonsense-mediated RNA decay in response to persistent DNA damage in noncycling cells. J. Biol. Chem. 292 (37), 15266–15276.
Li, T., Shi, Y., Wang, P., Guachalla, L. M., Sun, B., Joerss, T., Chen, Y.-S., Groth, M., Krueger, A., Platzer, M., Yang, Y.-G., Rudolph, K. L., and Wang, Z.-Q. (2015). Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay. The EMBO J. 34 (12), 1630–1647.
Hir, L., Nguyen, L. S., Huang, L., Ge, J., Chan, W., Bhalla, A. D., and Wilkinson, M. F. (2009). A UPF3-mediated regulatory switch that maintains RNA surveillance. Nat. Struct. Mol. Biol, 16 (7), 747–754.
Tarpey, P. S., Raymond, F. L., Nguyen, L. S., Rodriguez, J., Hackett, A., Vandeleur, L., Smith, R., Shoubridge, C., Edkins, S., Stevens, C., Meara, S. O., et al., (2007). Mutations in UPF3B, a member of the nonsense- mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nature Genetics, 39 (9), 1127–1133.
Denes, A. S., Jékely, G., Steinmetz, P. R. H., Raible, F., Snyman, H., Prud’homme, B., Ferrier, D. E. K., Balavoine, G., and Arendt, D. (2007). Molecular Architecture of Annelid Nerve Cord Supports Common Origin of Nervous System Centralization in Bilateria. Cell, 129 (2), 277–288.
Avery, P., Vicente-Crespo, M., Francis, D., Nashchekina, O., Alonso, C. R., and Palacios, I. M. (2011). Drosophila Upf1 and Upf2 loss of function inhibits cell growth and causes animal death in a Upf3-independent manner. RNA, 17, 624–638.
Barone, M. C., and Bohmann, D. (2013). Assessing Neurodegenerative Phenotypes in Drosophila Dopaminergic Neurons by Climbing Assays and Whole Brain Immunostaining. Jove, 74 (e50339), 1–5.
Malik, B. R. and Hodge, J. J. L. (2014). Drosophila Adult Olfactory Shock Learning. J. Vis. Exp. 90, 3–7.
Mery, F., Belay, A. T., K-C So, A., Sokolowski, M. B., Kawecki, T. J., and Robinson, G. E. (2007). Natural polymorphism affecting learning and memory in Drosophila. Proc. Natl. Acad. Sci., 104 (32), 13051–13055.
Langellotti, S., Romano, V., Romano, G., Klima, R., Feiguin, F., Cragnaz, L., Romano, M., and Baralle, F. E. (2016). A novel Drosophila model of TDP-43 proteinopathies : N-terminal sequences combined with the Q / N domain induce protein functional loss and locomotion defects. Disease Mod Mech, 9, 659–669.
Rolando, C., and Taylor, V. (2017). Non-canonical post-transcriptional RNA regulation of neural stem cell potential. Brain Plast. 3 (1): 111–116.
Chang, J., Kim, I. O., Ahn, J. S., Kwon, J. S., Jeon, S. H., and Kim, S. H. (2000). The CNS midline cells coordinate proper cell cycle progression and identity determination of the Drosophila ventral neuroectoderm. Developmental Biology, 227 (2), 307–323.
Spindler, S. R., and Hartenstein, V. (2010). The Drosophila neural lineages : a model system to study brain development and circuitry. Dev Genes Evol, 220, 1–10.
Jolly, L. A., Homan, C. C., Jacob, R., Barry, S., and Gecz, J. (2013). The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth. Hum Mol Genet., 22 (23), 4673–4687.
Bao, J., Vitting-seerup, K., Waage, J., and Tang, C. (2016). UPF2-Dependent Nonsense-Mediated mRNA Decay Pathway Is Essential for Spermatogenesis by Selectively Eliminating Longer 3 ’ UTR Transcripts. PLoS Genet. May 5; 12 (5): e1005863.
Lou, C., and Cook-andersen, H. (2016). The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay. Cell. 7; 165 (2): 382-95.
Wang, D., Zavadil, J., Martin, L., Parisi, F., Friedman, E., Levy, D., Harding, H., Ron, D., and Gardner, L. B. (2011). Inhibition of Nonsense-Mediated RNA Decay by the Tumor Microenvironment Promotes Tumorigenesis. Molecular and Cellular Biology, 31 (17), 3670–3680.
Nahm, M., and Lee, S. (2011). Characterization of the Rho GTPase-Activating Protein RhoGAP68F. Exp Neurobiol. Mar; 20 (1): 29–34.
Sanny, J., Chui, V., Langmann, C., Pereira, C., Zahedi, B., and Harden, N. (2006). Drosophila RhoGAP68F is a putative GTPase activating protein for RhoA participating in gastrulation. Dev Genes Evol. Sep; 216 (9): 543-50.
Nguyen, L. S., Jolly, L., Shoubridge, C., Chan, W. K., Huang, L., Laumonnier, F., and Raynaud, M. (2012). Transcriptome profiling of UPF3B / NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol. Psych, 17 (11), 1103–1115.
Iida, T., Saito, K., Katagiri, K., Kinashi, T., and Ohta, Y. (2016). The RacGAP protein FilGAP is a negative regulator of chemokine-promoted lymphocyte migration. FEBS Lett. May; 590 (10): 1395-408.
Xu, G. S., Lu, X. B., Huang, T. L., and Fan, J. (2016). ARHGAP24 inhibits cell cycle progression, induces apoptosis and suppresses invasion in renal cell carcinoma. Oncotarget Aug 9; 7 (32): 51829-51839.
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