Disrupted diencephalon development and neuropeptidergic pathways in zebrafish with autism-risk mutations

• 成果类型: Article
• 署名作者: Capps, Mary E. S.; Moyer, Anna J.; Conklin, Claire L.; Martina, Verdion; Olson, Emma G. Torija -; Klein, Morgan C.; Gannaway, William C.; Calhoun, Caleb C. S.; Vivian, Michael D.; Thyme, Summer B.
• 署名单位: University of Alabama System; University of Alabama Birmingham
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8962
• DOI: 10.1073/pnas.2402557122
• 发表日期: 2025-06-10
• 关键词: modulation; BEHAVIOR; oxytocin; disorder; genes; drugs

摘要

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.