The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel; Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.
Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.
Stem Cell Reports. 2024 Nov 12;19(11):1598-1619. doi: 10.1016/j.stemcr.2024.09.009. Epub 2024 Oct 31.
Mapping the essential pathways for neuronal differentiation can uncover new therapeutics and models for neurodevelopmental disorders. We thus utilized a genome-wide loss-of-function library in haploid human embryonic stem cells, differentiated into caudal neuronal cells. We show that essential genes for caudal neurogenesis are enriched for secreted and membrane proteins and that a large group of neurological conditions, including neurodegenerative disorders, manifest early neuronal phenotypes. Furthermore, essential transcription factors are enriched with homeobox (HOX) genes demonstrating synergistic regulation and surprising non-redundant functions between HOXA6 and HOXB6 paralogs. Moreover, we establish the essentialome of imprinted genes during neurogenesis, demonstrating that maternally expressed genes are non-essential in pluripotent cells and their differentiated germ layers, yet several are essential for neuronal development. These include Beckwith-Wiedemann syndrome- and Angelman syndrome-related genes, for which we suggest a novel regulatory pathway. Overall, our work identifies essential pathways for caudal neuronal differentiation and stage-specific phenotypes of neurological disorders.
绘制神经元分化的基本途径图可以揭示新的治疗方法和神经发育障碍的模型。因此，我们利用单倍体人类胚胎干细胞中的全基因组功能丧失文库，将其分化为尾侧神经元细胞。我们表明，尾侧神经发生的必需基因富集了分泌蛋白和膜蛋白，并且包括神经退行性疾病在内的一大组神经疾病表现出早期神经元表型。此外，必需转录因子与同源盒（HOX）基因富集，表明 HOXA6 和 HOXB6 同源物之间存在协同调节和惊人的非冗余功能。此外，我们在神经发生过程中建立了印迹基因的必需组，表明母系表达的基因在多能细胞及其分化的胚层中是非必需的，但有几个对神经元发育是必需的。其中包括 Beckwith-Wiedemann 综合征和 Angelman 综合征相关基因，我们为此提出了一个新的调控途径。总的来说，我们的工作确定了尾侧神经元分化的基本途径和神经疾病的特定阶段表型。
