Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Department of Neuroscience and Developmental Biology, Vienna Biocenter (VBC), University of Vienna, Vienna, Austria.
Nat Commun. 2024 Oct 5;15(1):8631. doi: 10.1038/s41467-024-52762-z.
Acquisition of specialized cellular features is controlled by the ordered expression of transcription factors (TFs) along differentiation trajectories. Here, we find a member of the Onecut TF family, ONECUT3, expressed in postmitotic neurons that leave their Ascl1/Onecut1/2 proliferative domain in the vertebrate hypothalamus to instruct neuronal differentiation. We combined single-cell RNA-seq and gain-of-function experiments for gene network reconstruction to show that ONECUT3 affects the polarization and morphogenesis of both hypothalamic GABA-derived dopamine and thyrotropin-releasing hormone (TRH) glutamate neurons through neuron navigator-2 (NAV2). In vivo, siRNA-mediated knockdown of ONECUT3 in neonatal mice reduced NAV2 mRNA, as well as neurite complexity in Onecut3-containing neurons, while genetic deletion of Onecut3/ceh-48 in C. elegans impaired neurocircuit wiring, and sensory discrimination-based behaviors. Thus, ONECUT3, conserved across neuronal subtypes and many species, underpins the polarization and morphological plasticity of phenotypically distinct neurons that descend from a common pool of Ascl1 progenitors in the hypothalamus.
细胞特化特征的获得受转录因子（TFs）沿分化轨迹的有序表达所控制。在这里，我们发现了一个 Onecut TF 家族成员，ONECUT3，在离开其增殖域的有丝分裂后神经元中表达，该增殖域位于脊椎动物下丘脑的 Ascl1/Onecut1/2 中，以指示神经元分化。我们结合单细胞 RNA-seq 和基因网络重建的功能获得实验表明，ONECUT3 通过神经元导航蛋白-2（NAV2）影响下丘脑 GABA 衍生的多巴胺和促甲状腺素释放激素（TRH）谷氨酸神经元的极化和形态发生。在体内，用 siRNA 介导的 ONECUT3 敲低会减少新生小鼠中的 NAV2 mRNA，以及包含 ONECUT3 的神经元中的神经突复杂性，而在秀丽隐杆线虫中，对 Onecut3/ceh-48 的基因缺失会损害神经回路连接和基于感觉辨别行为。因此，ONECUT3 在神经元亚型和许多物种中保守，为来自下丘脑的共同 Ascl1 祖细胞池的表型不同的神经元的极化和形态可塑性提供支持。
