Zebrafish Models
Dr. Bettina Schmid
Group Leader
Feodor-Lynen-Str. 17
81377 München

bettina.schmid@dzne.de
 +49 89 4400-46511

Areas of investigation/research focus

The zebrafish is a small tropical freshwater fish, which is genetically amenable. Zebrafish are easily bred in a laboratory environment and each female can give hundreds of eggs each week. The embryos and larvae are transparent ideally suited to identify gene function, perform non-invasive in vivo imaging, and drug testing. The research group Zebrafish Models is using genetic Zebrafish models to identify gene function and to study molecular mechanisms of the neurodegenerative diseases Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Genetic zebrafish models are generated by cutting-edge CRISPR/Cas9 genome editing technology to generate knock-out animals, introduce disease-associated mutations, or modify endogenous proteins. The Zebrafish Models group was one of the first groups applying this technology to modify the zebrafish genome (Hruscha et al., Development 2015). The main focus of the Zebrafish Models group is the elucidation of the physiological and pathophysiological functions of RNA-binding proteins in ALS and the physiological function of AD-associated proteins BACE 1 and -2 and the Amyloid Precursor Protein (APP).
By running a large modern state-of-art zebrafish facility we further provide a technology platform and knowhow for collaborating research groups within the DZNE.

 more Infos

The transparent zebrafish larvae enable us to visualize what is happening inside the organism non-invasively. By labeling different cell types we can visualize the interaction between these cell types in vivo. In the example below, we visualize the vasculature in a live fish with a green fluorescent reporter and are able to follow the developing vasculature.

Zebrafish that lack functional TDP-43 (a gene mutated and aggregated in almost all cases of amyotrophic lateral sclerosis) show a dramatic mis-patterning of the vasculature (shown in green - on the right in mutants compared to wildtype on the left). The analysis of the TDP-43 mutant fish uncovered this very unexpected link between neurodegeneration and the vasculature. The molecular mechanism leading to vascular defects have been elucidated and were also affected in ALS patients. These targets of TDP-43 function might provide a suitable alternative therapeutic strategy to treat ALS.
By studying disease gene function and the consequences of mutations in disease genes the Zebrafish Models group contribute in the general understanding of the molecular mechanisms of disease.

Key Publications

Alexander Hruscha, Peter Krawitz, Alexandra Rechenberg, Verena Heinrich, Jochen Hecht, Christian Haass, Bettina Schmid. Efficient CRISPR/Cas9 genome editing with low off-target effects in zebrafish. Development (Cambridge). 2013 Dec 14; 140:4982-4987. doi: 10.1242/dev.099085
Schmid B, Hruscha A, Hogl S, Banzhaf-Strathmann J, Strecker K, van der Zee J, Teucke M, Eimer S, Hegermann J, Kittelmann M, Kremmer E, Cruts M, Solchenberger B, Hasenkamp L, van Bebber F, Van Broeckhoven C, Edbauer D, Lichtenthaler SF, Haass C. Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A. 2013 Mar 26; 110:4986-91. doi: 10.1073/pnas.1218311110
Frauke Van Bebber, Alexander Hruscha, Michael Willem, Bettina Schmid, Christian Haass. Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes. Journal of Neurochemistry. 2013 Oct 31; 127:471-481. doi: 10.1111/jnc.12198
Dominik Paquet, Ratan Bhat, Astrid Sydow, Eva-Maria Mandelkow, Stefan Berg, Sven Hellberg, Johanna Fälting, Martin Distel, Reinhard W. Köster, Bettina Schmid, Christian Haass. A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. Journal of Clinical Investigation. 2009 Apr 30; 119:1382-1395. doi: 10.1172/JCI37537
Schmid B, Furthauer M, Connors SA, Trout J, Thisse B, Thisse C, et al. Equivalent genetic roles for bmp7/snailhouse and bmp2b/swirl in dorsoventral pattern formation. Development. 2000 Jan 01; 127:957-67.

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