Functional studies of novel genes in adult neurogenesis in the annual fish Nothobranchius furzeri
Final Report Abstract
The initial goal of this grant was to analyze novel genes for their potential role in neurogenesis in the short-lived Killifish N. furzeri. The underlying hypothesis was that changes of expression levels of potential novel target genes, as they occur during ageing of the brain, are directly correlated to the decline of neurogenesis during ageing. Hence, acute or genetic manipulation of those genes could have a direct influence on the function of (neuronal) stem cells. During the runtime of the project some problems occurred (stop of animal experimentation for several months in the year 2016) which led us to change the work program and used models. The use of zebrafish embryos for the acute manipulation of ZNF367 gene expression levels and the resulting influence on neurogenesis together with analyses of mouse ESC, expressing biotin-tagged ZFP367, allowed us already to confirm the important role of this putative transcription factor on neurogenesis and differentiation. With this we fulfilled two main goals of the projects. Further experiments like the analysis of complex partners of ZNF367 in different subcellular compartments (i.e. nucleus and cytoplasm) will give us additional important information about the influence of spatial and temporal expression of ZNF367 on stem cells and differentiation. With the generation of the the N. furzeri Kif5α:sponge-miR25 and the ZNF367del_ex1 CRISPR/Cas9 line the third aim of this project was reached. The sponge-miR-29 line allowed us to identify an important role of miR-29 in controlling iron homeostasis in the brain via regulation of IRP2. the ZNF367del_ex1 CRISPR/Cas9 line will allow us the phenotypic and molecular characterization of the loss of function in vivo. We will now finish the mentioned experiments on ZNF367 and prepare publication. Even though the project was overshadowed by unpredictable problems, we were able to define alternative strategies and to analyze one of the proposed target genes in depth. We have now established all the methods and tools required for functional studies of additional genes from our candidate list. This will allow us the in depth study of additional targets in line with the main goals of this project.
Publications
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(2016) Discovering miRNA Regulatory Networks in Holt-Oram Syndrome Using a Zebrafish Model. Front Bioeng Biotechnol, 4:60
D'Aurizio R, Russo F, Chiavacci E, Baumgart M, Groth M, D'Onofrio M, Arisi I, Rainaldi G, Pitto L, Pellegrini M
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(2016) Longitudinal RNA-Seq Analysis of Vertebrate Aging Identifies Mitochondrial Complex I as a Small-Molecule-Sensitive Modifier of Lifespan. Cell Syst, 2(2):122-32
Baumgart M, Priebe S, Groth M, Hartmann N, Menzel U, Pandolfini L, Koch P, Felder M, Ristow M, Englert C, Guthke R, Platzer M, Cellerino A
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(2017) A miRNA catalogue and ncRNA annotation of the short-living fish Nothobranchius furzeri. BMC Genomics, 18(1):693
Baumgart M, Barth E, Savino A, Groth M, Koch P, Petzold A, Arisi I, Platzer M, Marz M, Cellerino A
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(2017) Age-dependent increase of oxidative stress regulates microRNA-29 family preserving cardiac health. Sci Rep, 7(1):16839
Heid J, Cencioni C, Ripa R, Baumgart M, Atlante S, Milano G, Scopece A, Kuenne C, Guenther S, Azzimato V, Farsetti A, Rossi G, Braun T, Pompilio G, Martelli F, Zeiher AM, Cellerino A, Gaetano C, Spallotta F
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(2017) MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging. BMC Biol, 15(1):9
Ripa R, Dolfi L, Terrigno M, Pandolfini L, Savino A, Arcucci V, Groth M, Terzibasi Tozzini E, Baumgart M, Cellerino A
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(2018) Integrative analysis of differentially expressed genes and miRNAs predicts complex T3- mediated protective circuits in a rat model of cardiac ischemia reperfusion. Sci Rep, 8(1):13870
Forini F, Nicolini G, Kusmic C, D'Aurizio R, Rizzo M, Baumgart M, Groth M, Doccini S, Iervasi G, Pitto L
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(2018) The microRNA miR-21 Is a Mediator of FGF8 Action on Cortical COUP-TFI Translation. Stem Cell Reports, 11(3):756-769
Terrigno M, Bertacchi M, Pandolfini L, Baumgart M, Calvello M, Cellerino A, Studer M, Cremisi F
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(2019) Age-related central regulation of orexin and NPY in the short-lived African Killifish Nothobranchius furzeri. J Comp Neurol, 527(9):1508-1526
Montesano A, Baumgart M, Avallone L, Castaldo L, Lucini C, Tozzini ET, Cellerino A, D'Angelo L, de Girolamo P
