Generation of zebrafish mutants in homologs of ASD risk genes

With more than 100 genes causally linked to autism spectrum disorders (ASDs), the next major challenge is to discover the neurodevelopmental consequences of different genetic mutations. An ideal system would permit the unbiased phenotyping of effects of ASD gene mutations on neural development and brain function. Zebrafish enable each of these goals. In zebrafish, whole brain development can be quantitatively analyzed at cellular resolution, providing an opportunity to systematically analyze the effects of gene mutations on brain architecture and cellular composition. Furthermore, neuronal activity can be recorded brain-wide, disclosing effects of gene mutations on neuronal signaling.

To enable these specialized techniques to be performed by multiple laboratories, Harold Burgess’ laboratory will use CRISPR-based technology to generate mutations in zebrafish homologs of five genes strongly associated with risk for ASD: ARID1B, CHD8, DYRK1A, GRIN2B and SCN2A, including in paralogs of DYRK1A and GRIN2B. Mutant lines will be validated using RT-PCR, then deposited in the Zebrafish International Resource Center (ZIRC) for unrestricted distribution. This freely available resource of zebrafish genetic mutants will provide access to a common set of validated mutant alleles, facilitating deep phenotyping by laboratories internationally with specialized technical expertise.