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
Department of Neurobiology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294.
Proc Natl Acad Sci U S A. 2025 Jun 10;122(23):e2402557122. doi: 10.1073/pnas.2402557122. Epub 2025 Jun 3.
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 and , 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.
数百种人类突变与自闭症及相关疾病有关，但其中许多突变基因在脊椎动物神经发育过程中的功能尚不清楚。我们生成了27个斑马鱼突变体，这些突变体具有推定的蛋白质截短突变或对应于17个人类基因中自闭症风险等位基因的特定错义变体。我们观察到幼虫阶段的基线和刺激驱动的行为变化，以及作为幼鱼测试的品系中的社交行为差异。对全脑活动进行成像显示，无关基因和中的突变具有几乎相同的活动图谱，主要表现为丘脑和中脑的活动增加。17个风险基因中的7个发生突变导致大脑大小出现显著差异，其中3例局限于间脑，其他情况则更广泛。通过RNA测序，我们进一步确定了三个突变体观察到的表型的分子驱动因素，确定了神经肽信号传导、神经元成熟和细胞增殖中可靶向的破坏。这种多模式筛选确定了可能导致自闭症易感性的脑区、细胞类型和分子途径。
