Dataset Information

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.

ABSTRACT: Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.

SUBMITTER: Weinschutz Mendes H

PROVIDER: S-EPMC10277173 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.

Weinschutz Mendes Hellen H Neelakantan Uma U Liu Yunqing Y Fitzpatrick Sarah E SE Chen Tianying T Wu Weimiao W Pruitt April A Jin David S DS Jamadagni Priyanka P Carlson Marina M Lacadie Cheryl M CM Enriquez Kristen D KD Li Ningshan N Zhao Dejian D Ijaz Sundas S Sakai Catalina C Szi Christina C Rooney Brendan B Ghosh Marcus M Nwabudike Ijeoma I Gorodezky Andrea A Chowdhury Sumedha S Zaheer Meeraal M McLaughlin Sarah S Fernandez Joseph M JM Wu Jia J Eilbott Jeffrey A JA Vander Wyk Brent B Rihel Jason J Papademetris Xenophon X Wang Zuoheng Z Hoffman Ellen J EJ

Cell reports 20230317 3

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while reg ...[more]

PMID: 36933215

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Project description:Ankyrin repeat and kinase domain containing 1 (ANKK1) is a member of the receptor-interacting protein serine/threonine kinase family, known to be involved in cell proliferation, differentiation and activation of transcription factors. Genetic variation within the ANKK1 locus is suggested to play a role in vulnerability to addictions. However, ANKK1 mechanism of action is still poorly understood. It has been suggested that ANKK1 may affect the development and/or functioning of dopaminergic pathways. To test this hypothesis, we generated a CRISPR-Cas9 loss of function ankk1 zebrafish line causing a 27 bp insertion that disrupts the ankk1 sequence introducing an early stop codon. We found that ankk1 transcript levels were significantly lower in ankk1 mutant (ankk127ins ) fish compared to their wild type (ankk1 +/+) siblings. In ankk1 +/+ adult zebrafish brain, ankk1 protein was detected in isocortex, hippocampus, basolateral amygdala, mesencephalon, and cerebellum, resembling the mammalian distribution pattern. In contrast, ankk1 protein was reduced in the brain of ankk127ins/27ins fish. Quantitative polymerase chain reaction analysis revealed an increase in expression of drd2b mRNA in ankk127ins at both larval and adult stages. In ankk1 +/+ adult zebrafish brain, drd2 protein was detected in cerebral cortex, cerebellum, hippocampus, and caudate homolog regions, resembling the pattern in humans. In contrast, drd2 expression was reduced in cortical regions of ankk127ins/27ins being predominantly found in the hindbrain. No differences in the number of cell bodies or axonal projections detected by anti-tyrosine hydroxylase immunostaining on 3 days post fertilization (dpf) larvae were found. Behavioral analysis revealed altered sensitivity to effects of both amisulpride and apomorphine on locomotion and startle habituation, consistent with a broad loss of both pre and post synaptic receptors. Ankk127ins mutants showed reduced sensitivity to the effect of the selective dopamine receptor antagonist amisulpride on locomotor responses to acoustic startle and were differentially sensitive to the effects of the non-selective dopamine agonist apomorphine on both locomotion and habituation. Taken together, our findings strengthen the hypothesis of a functional relationship between ANKK1 and DRD2, supporting a role for ANKK1 in the maintenance and/or functioning of dopaminergic pathways. Further work is needed to disentangle ANKK1's role at different developmental stages.

Dataset Information

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.

Publications

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.

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