Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation
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 <i>NFI</i> 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.
Authors
- Xing Tang (ORCID: https://orcid.org/0000-0001-5313-9901)
- Heng Du (ORCID: https://orcid.org/0000-0002-2661-5818)
- Zhimin Lao
- Richard M. Gronostajski (ORCID: https://orcid.org/0000-0003-4264-208X)
- Xuyao Chang (ORCID: https://orcid.org/0000-0002-7646-9521)
- Linda J. Richards (ORCID: https://orcid.org/0000-0002-7590-7390)
- Alexandra L. Joyner (ORCID: https://orcid.org/0000-0001-7090-9605)
- Anjana Krishnamurthy (ORCID: https://orcid.org/0000-0002-4584-1722)
- Jason Tchieu (ORCID: https://orcid.org/0000-0002-9793-9836)
- Elena Albizzati (ORCID: https://orcid.org/0000-0001-6087-0014)
- Song-Hai Shi
- Choong H. Lee (ORCID: https://orcid.org/0000-0001-8711-4307)
- Jiajun Yang (ORCID: https://orcid.org/0000-0002-0922-3783)
- Xiaojuan Yu (ORCID: https://orcid.org/0000-0003-4600-7841)
- Guohua Yuan
- Jian Ma
- XP Zhang
- Z. Zhao (ORCID: https://orcid.org/0009-0008-7694-4987)
- Yinqing Li
- Qiangqiang Zhang
- Jiangyang Zhang
- Shuhan Hu
- Yudan Chi
- Xiaohui Lv
Institutions
- Buffalo State University (US)
- Cincinnati Children's Hospital Medical Center (US)
- nLIGHT (United States) (US)
- Memorial Sloan Kettering Cancer Center (US)
- Washington University in St. Louis (US)
- Nankai University (CN)
- Fudan University (CN)
- Yangtze River Delta Physics Research Center (China) (CN)
- Chinese Institute for Brain Research (CN)
- University School (US)
- Huashan Hospital (CN)
- Center for Life Sciences (CN)
- New York University (US)
- University of Cincinnati (US)
- University at Buffalo, State University of New York (US)
- Zhejiang University (CN)
- University of Cincinnati Medical Center (US)
- Tsinghua University (CN)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-27
- DOI
- https://doi.org/10.64898/2025.12.27.696675
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00