Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation
Year: 2025
Type: preprint
Abstract: SUMMARY Nuclear Factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), and consequently neocortical development in a dose-dependent manner. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and neocortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental stage-dependent precocious productions of diverse neural progenies. Moreover, NFIs exhibit a positive auto-regulation and progressive increase in expression, and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development. HIGHLIGHTS NFIs affect human RGP temporal development coinciding with patient phenotypes. NFI removal protracts RGP lineage progression and lifespan with excessive progeny output. NFI overexpression accelerates RGP lineage progression with precocious progeny output. NFIs regulate distinct temporal-specific targets underlying RGP lineage progression.
Authors: Qiangqiang Zhang, Guohua Yuan, Elena Albizzati, Jiajun Yang, Zhe Zhao, Xiangyu Yu, Xuyao Chang, Choong Heon Lee, Heng Du, Zhimin Lao, Anjana Krishnamurthy, Xiuli Zhang, Xiaohui Lv, Xing Tang, Shuhan Hu, Yudan Chi, Jian Ma, Richard M. Gronostajski, Linda J. Richards, Jiangyang Zhang, Alexandra L. Joyner, Jason Tchieu, Yinqing Li, Song-Hai Shi
Institutions: Memorial Sloan Kettering Cancer Center, Center for Life Sciences, Tsinghua University, State Key Laboratory of Molecular Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, New York University, Nankai University, Laboratoire de Biotechnologies Agroalimentaire et Environnementale, Shanghai Medical College of Fudan University, Fudan University, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Frontiers Center for Brain Science of the Ministry of Education, University at Buffalo, State University of New York, Washington University in St. Louis
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7117420481