Dang Nghi D P, Barcus Alexia K, Conklin Claire L, Truong Thinh Q, Vivian Michael D, Wang Jun, Thomas Holly R, Parant John M, Yeo Nan Cher, Thyme Summer B
Department of Pharmacology and Toxicology, The University of Alabama at Birmingham Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, University of Massachusetts, Worcester, MA 01605, USA.
G3 (Bethesda). 2025 May 23. doi: 10.1093/g3journal/jkaf115.
Mutations in the transcription factor EBF3 result 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 zebrafish ebf3a loss-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. RNA-sequencing of developing larvae revealed significant downregulation of genes that mark olfactory sensory neurons, the lateral line, and cerebellar Purkinje neurons. Corroborating the RNA-sequencing, staining revealed fewer lateral line neuromasts and reduced Parvalbumin signal in the cerebellum. 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.
转录因子EBF3的突变会导致一种神经发育障碍，动物模型研究表明它在神经元分化中起关键作用。然而，其功能丧失所破坏的分子途径和神经元类型尚未得到充分研究。这些变化对行为和大脑活动的影响也未可知。在此，我们构建并鉴定了一个斑马鱼ebf3a功能丧失突变体。我们发现了形态和神经表型，包括整体脑尺寸变小，尤其是下丘脑、小脑和后脑。脑功能也受到损害，小脑活动强烈增加，基线时以及对视觉和听觉刺激的反应中出现异常行为。对发育中的幼虫进行RNA测序发现，标记嗅觉感觉神经元、侧线和小脑浦肯野神经元的基因显著下调。与RNA测序结果一致，染色显示侧线神经丘较少，小脑中的小白蛋白信号减少。这项研究为确定哪些下游途径是观察到的表型出现的基础奠定了基础，并建立了多个强大的表型，可为药物筛选提供依据。
