Zebrafish models

Zebrafish are increasingly being used to study neurodevelopmental disorders, including autism spectrum disorder (ASD). Zebrafish are genetically tractable, transparent during development and amenable to high-throughput phenotyping, making them a valuable experimental platform to interrogate the biological mechanisms by which genetic mutations affect phenotype and to identity potential therapeutic targets.

Use of mutant zebrafish to study gene function, however, has proven challenging. One reason is that genetic manipulations aimed at producing gene loss-of-function may still leave significant amounts of mRNA produced by the targeted gene, indicating that loss of function of the targeted gene may not have been entirely achieved1.

To address this issue and facilitate ASD research using zebrafish, SFARI is now curating zebrafish lines with mutations in zebrafish paralogs of 12 ASD risk genes in which gene loss-of-function is validated by directly measuring mRNA or protein levels (where antibodies are available) rather than by assessing phenotype. These include three previously existing zebrafish lines, as well as lines that have been deposited and/or validated upon SFARI request, and lines that have been created and validated de novo with SFARI support.

All lines curated by SFARI are listed below and can be found at the Zebrafish International Research Center (ZIRC). Interested investigators should contact ZIRC directly to obtain access.

Available zebrafish models

ARID1B

  • Zebrafish gene: arid1b
ZIRC allele: y607
Created by: Harold Burgess (National Institute of Child Health and Human Development)
Method: CRISPR
Validation: Quantitative polymerase chain reaction (QPCR)

FMR1

  • Zebrafish gene: fmr1
ZIRC allele: hu2787
Created by: René F. Ketting (University Medical Center Utrecht)2
Method: N-ethyl-N-nitrosourea (ENU) mutagenesis
Validation: Western blot, immunocytochemistry

  • Zebrafish gene: fmr1
ZIRC allele: hu2898
Created/described by: René F. Ketting, Ph.D. (University Medical Center Utrecht)2
Method: ENU mutagenesis
Validation: Western blot, immunocytochemistry

MECP2

  • Zebrafish gene: mecp2
ZIRC allele: fh232
Created/described by: Cecilia Moens, Ph.D. (Fred Hutchinson Cancer Research Center)3
Method: ENU mutagenesis
Validation: Western blot

PTEN

  • Zebrafish gene: ptena
ZIRC allele: hu1864
Created by: Jeroen den Hertog, Ph.D. (Leiden University)4
Method: ENU mutagenesis
Validation: Western blot
  • Zebrafish gene: ptenb
ZIRC allele: hu1435
Created by: Jeroen den Hertog, Ph.D. (Leiden University)4
Method: ENU mutagenesis
Validation: Western blot

Future zebrafish models

The following lines are expected to be available later this year:

  • CHD8
  • CNTNAP2
  • DYRK1A
  • GRIN2B
  • NRXN1
  • SCN2A
  • SHANK3
  • SYNGAP1

For more information about these lines, and general inquiries about SFARI’s experimental models, please contact: models@simonsfoundation.org.

References

  1. Anderson J.L. et al. PLoS Genet. 13, e1007105 (2017) PubMed
  2. den Broeder M.J. et al. PLoS One 4, e7910 (2009) PubMed
  3. Pietri T. et al. Front. Neural Circuits 7, 118 (2013) PubMed
  4. Stumpf M. and den Hertog J. PLoS One 11, e0148508 (2016) PubMed
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