Pan Tong, Lin Grace, Li Xuan, VanHeyningen Debora, Walker John Clay, Kohli Sahej, Saravanan Aiswarya, Kondur Amrita, Jaklic Daniel C, Pantoja-Gutierrez Saul, Vaid Shivanshi, Sturza Julie, Inoki Ken, Imamichi Tomozumi, Chang Weizhong, Dang Louis T
Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
bioRxiv. 2025 May 14:2025.05.13.653911. doi: 10.1101/2025.05.13.653911.
Biallelic pathogenic variants in , an upstream regulator of the mechanistic target of rapamycin (mTOR) pathway, result in megalencephaly, drug-resistant epilepsy, and severe intellectual disability. This study explores how mTOR pathway hyperactivity alters cell fate specification in dorsal and ventral forebrain development using knock-out human stem cell derived brain organoids. In both dorsal and ventral forebrain knock-out organoids, neurogenesis is delayed, with a predilection for progenitor renewal and proliferation and an increase in outer radial glia. Ventrally, interneuron subtypes shift to an increase in neuropeptide-Y expressing cells. Inhibition of the mTOR pathway with rapamycin results in rescue for most phenotypes. When mTOR pathway variants are present in all cells of the developing brain, overproduction of interneurons and altered interneuron cell fate may underlie mechanisms of megalencephaly, epilepsy, and cognitive impairment. Our findings suggest mTOR inhibition during fetal brain development as a potential therapeutic strategy in deficiency.
雷帕霉素作用机制靶点（mTOR）通路的上游调节因子 中的双等位基因致病性变异会导致巨头畸形、耐药性癫痫和严重智力障碍。本研究利用 基因敲除的人干细胞衍生脑类器官，探讨了mTOR通路的过度活跃如何改变背侧和腹侧前脑发育中的细胞命运特化。在背侧和腹侧前脑 基因敲除类器官中，神经发生均延迟，倾向于祖细胞更新和增殖，外侧放射状胶质细胞增加。在腹侧，中间神经元亚型转变为表达神经肽Y的细胞增加。用雷帕霉素抑制mTOR通路可挽救大多数表型。当mTOR通路变异存在于发育中大脑的所有细胞中时，中间神经元的过度产生和中间神经元细胞命运的改变可能是巨头畸形、癫痫和认知障碍机制的基础。我们的研究结果表明，在胎儿脑发育期间抑制mTOR作为 缺陷的一种潜在治疗策略。
