Modelling human disease

Zebrafish are increasingly becoming a popular model for translational research aimed at understanding and treating human disease. With the development of gene editing systems such as CRISPR/Cas9, targeted knock-ins, knock-outs and other specific genetic modifications are becoming more straightforward. Our lab has established collaborations with clinicians (and indeed we have clinicians studying for PhDs in our lab) and together we are studying fish orthologues of candidate disease genes from human patients. We aim to use studies in fish to determine if genetic mutations are really causative of disease phenotypes, help place genes in genetic pathways through epistasis analyses and understand the cellular and molecular bases of disease phenotypes.

The lab currently works on developing zebrafish models for quite a diverse range of human conditions including ciliopathies, neurodegenerative disorders, coloboma, microphthalmia and other eye abnormalities and, in collaboration with the Rihel, Dreosti and Hoffman labs, autism spectrum disorders.

RELATED PUBLICATION SUMMARIES

Publication summaries

A zebrafish model for branchio-oculo-facial syndrome - a condition affecting eye formation

Muscles but no movements - identification of a new gene required for muscle function

MODELLING HUMAN DISEASE PUBLICATIONS

Karin Tuschl, Esther Meyer, Leonardo E. Valdivia, Ningning Zhao, Chris Dadswell, Alaa Abdul-Sada, Christina Y. Hung, Michael A. Simpson, W. K. Chong, Thomas S. Jacques, Randy L. Woltjer, Simon Eaton, Allison Gregory, Lynn Sanford, Eleanna Kara, Henry Houlden, Stephan M. Cuno, Holger Prokisch, Lorella Valletta, Valeria Tiranti, Rasha Younis, Eamonn R. Maher, John Spencer, Ania Straatman-Iwanowska, Paul Gissen, Laila A. M. Selim, Guillem Pintos-Morell, Wifredo Coroleu-Lletget, Shekeeb S. Mohammad, Sangeetha Yoganathan, Russell C. Dale, Maya Thomas, Jason Rihel, Olaf A. Bodamer, Caroline A. Enns, Susan J. Hayflick, Peter T. Clayton, Philippa B. Mills, Manju A. Kurian & Stephen W. Wilson (2016)
Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia
Nat Commun. 2016 May 27;7:11601. doi: 10.1038/ncomms11601.

Hoffman EJ, Turner KJ, Fernandez JM, Cifuentes D, Ghosh M, Ijaz S, Jain RA, Kubo F, Bill BR, Baier H, Granato M, Barresi MJ, Wilson SW, Rihel J, State MW, Giraldez AJ. (2016)
Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.
Neuron. 2016 Jan 27. pii: S0896-6273(15)01167-8. doi: 10.1016/j.neuron.2015.12.039.

Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins TA, Giacomotto J, Zhao T, Mueller T, Bader PI, Cheung SW, Stankiewicz P, Bain NL, Hackett A, Reddy CC, Mechaly AS, Peers B, Wilson SW, Lenhard B, Bally-Cuif L, Gecz J, Becker TS, Rinkwitz S. (2015)
Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.
Hum Genet. 2015 Nov;134(11-12):1163-82. doi: 10.1007/s00439-015-1594-x

Naville M, Ishibashi M, Ferg M, Bengani H, Rinkwitz S, Krecsmarik M, Hawkins TA, Wilson SW, Manning E, Chilamakuri CS, Wilson DI, Louis A, Lucy Raymond F, Rastegar S, Strähle U, Lenhard B, Bally-Cuif L, van Heyningen V, FitzPatrick DR, Becker TS, Roest Crollius H. (2015)
Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome. Nat Commun. 2015 Apr 24;6:6904. doi: 10.1038/ncomms7904.

Mahmood F, Fu S, Cooke J, Wilson SW, Cooper JD, Russell C. (2013)
A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation.
Brain. 2013 May;136(Pt 5):1488-507

Gestri G, Osborne RJ, Wyatt AW, Gerrelli D, Gribble S, Stewart H, Fryer A, Bunyan DJ, Prescott K, Collin JR, Fitzgerald T, Robinson D, Carter NP, Wilson SW, Ragge NK. (2009)
Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators.
Hum Genet. 126:791-803.

Hawkins TA, Haramis AP, Etard C, Prodromou C, Vaughan CK, Ashworth R, Ray S, Behra M, Holder N, Talbot WS, Pearl LH, Strähle U, Wilson SW. (2008)
The ATPase-dependent chaperoning activity of Hsp90a regulates thick filament formation and integration during skeletal muscle myofibrillogenesis.
Development 135:1147-1156

Navratilova, P., Fredman, D., Hawkins, T.A., Turner, K., Lenhard, B., Becker, T. S., (2008)
Systematic human/zebrafish comparative identification of cis-regulatory activity around vertebrate developmental transcription factor genes
Dev Biol. 327:526-540