PUBLICATION
Disrupted diencephalon development and neuropeptidergic pathways in zebrafish with autism-risk mutations
- Authors
- Capps, M.E.S., Moyer, A.J., Conklin, C.L., Martina, V., Torija-Olson, E.G., Klein, M.C., Gannaway, W.C., Calhoun, C.C.S., Vivian, M.D., Thyme, S.B.
- ID
- ZDB-PUB-250604-5
- Date
- 2025
- Source
- Proceedings of the National Academy of Sciences of the United States of America 122: e2402557122e2402557122 (Journal)
- Registered Authors
- Thyme, Summer
- Keywords
- CRISPR/Cas9, autism spectrum disorder, diencephalon, neuropeptide, zebrafish
- Datasets
- GEO:GSE253405
- MeSH Terms
-
- Signal Transduction
- Animals
- Neuropeptides*/genetics
- Neuropeptides*/metabolism
- Autistic Disorder*/genetics
- Autistic Disorder*/metabolism
- Disease Models, Animal
- Diencephalon*/embryology
- Diencephalon*/growth & development
- Diencephalon*/metabolism
- Mutation*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Humans
- Zebrafish*/genetics
- PubMed
- 40460132 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Capps, M.E.S., Moyer, A.J., Conklin, C.L., Martina, V., Torija-Olson, E.G., Klein, M.C., Gannaway, W.C., Calhoun, C.C.S., Vivian, M.D., Thyme, S.B. (2025) Disrupted diencephalon development and neuropeptidergic pathways in zebrafish with autism-risk mutations. Proceedings of the National Academy of Sciences of the United States of America. 122:e2402557122e2402557122.
Abstract
Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neurodevelopment are unclear. We generated 27 zebrafish mutants with presumptive protein-truncating mutations or specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated genes kmt5b and hdlbpa, defined by increased activity mainly in the thalamus and mesencephalon. Mutating 7 of the 17 risk genes resulted in substantial brain size differences, localized to the diencephalon in three cases and more widespread in others. Using RNA sequencing, we further defined molecular drivers of the observed phenotypes for three mutants, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multimodal screen nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping