Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

Capps, Mary E.S.; Moyer, Anna J.; Conklin, Claire L.; Martina, Verdion; Torija-Olson, Emma G.; Klein, Morgan C.; Gannaway, William C.; Calhoun, Caleb C.S.; Vivian, Michael D.; Thyme, Summer B.

doi:10.1101/2024.01.18.576309

Cited by 5 publications

References 104 publications

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Removal of developmentally regulated microexons has a minimal impact on larval zebrafish brain morphology and function

Calhoun,

Capps,

Muya

et al. 2024

Preprint

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Microexon splicing is a vertebrate-conserved process through which small, often in-frame, exons are differentially included during brain development and across neuron types. Although the protein sequences encoded by these exons are highly conserved and can mediate interactions, the neurobiological functions of only a small number have been characterized. To establish a more generalized understanding of their roles in brain development, we used CRISPR/Cas9 to remove 45 microexons in zebrafish and assessed larval brain activity, morphology, and behavior. Most mutants had minimal or no phenotypes at this developmental stage. Among previously studied microexons, we uncovered baseline and stimulus-driven phenotypes for two microexons (meA and meB) inptprdand reduced activity in the telencephalon in thetenm3B0isoform. Although mild, neural phenotypes were discovered for several microexons that have not been previously characterized, including inppp6r3, sptan1, dop1a, rapgef2, dctn4, vti1a, andmeaf6. This study establishes a general approach for investigating conserved alternative splicing events and prioritizes microexons for downstream analysis.

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Removal of developmentally regulated microexons has a minimal impact on larval zebrafish brain morphology and function

Calhoun,

Capps,

Muya

et al. 2024

Preprint

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Dynamic convergence of autism disorder risk genes across neurodevelopment

Fernandez Garcia,

Retallick-Townsley,

Pruitt

et al. 2024

Preprint

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Over a hundred risk genes underlie risk for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets to increase ASD risk is unknown. To test the hypothesis that cellular context impacts the nature of convergence, here we apply a pooled CRISPR approach to target 29 ASD loss-of-function genes in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level and network-level analyses) demonstrate that convergence is greatest in mature glutamatergic neurons. Convergent effects are dynamic, varying in strength, composition, and biological role between cell types, increasing with functional similarity of the ASD genes examined, and driven by cell-type-specific gene co-expression patterns. Stratification of ASD genes yield targeted drug predictions capable of reversing gene-specific convergent signatures in human cells and ASD-related behaviors in zebrafish. Altogether, convergent networks downstream of ASD risk genes represent novel points of individualized therapeutic intervention.

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Disrupted development of sensory systems and the cerebellum in a zebrafishebf3amutant

Dang,

Conklin,

Truong

et al. 2024

Preprint

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Mutations in the transcription factorEBF3results in a neurodevelopmental disorder, and studies in animal models indicate that it has a critical role in neuronal differentiation. The molecular pathways and neuron types disrupted by its loss, however, have not been thoroughly investigated. Nor have the outcomes of these changes on behavior and brain activity. Here, we generated and characterized a zebrafishebf3aloss-of-function mutant. We discovered morphological and neural phenotypes, including an overall smaller brain size, particularly in the hypothalamus, cerebellum, and hindbrain. Brain function was also compromised, with activity strongly increased in the cerebellum and abnormal behavior at baseline and in response to visual and acoustic stimuli. From RNA-sequencing of developing larvae, notable changes included significant downregulation of genes that mark olfactory sensory neurons, the lateral line, and cerebellar Purkinje neurons. This study sets the stage for determining which downstream pathways underlie the emergence of the observed phenotypes and establishes multiple strong phenotypes that could form the basis of a drug screen.

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Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

Cited by 5 publications

References 104 publications

Removal of developmentally regulated microexons has a minimal impact on larval zebrafish brain morphology and function

Removal of developmentally regulated microexons has a minimal impact on larval zebrafish brain morphology and function

Dynamic convergence of autism disorder risk genes across neurodevelopment

Disrupted development of sensory systems and the cerebellum in a zebrafishebf3amutant

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