Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation

Zhang, Q.; Yuan, G.; Albizzati, E.; Yang, J.; Zhao, Z.; Yu, X.; Chang, X.; Lee, C. H.; Du, H.; Lao, Z.; Krishnamurthy, A.; Zhang, X.; Lv, X.; Tang, X.; Hu, S.; Chi, Y.; Ma, J.; Gronostajski, R. M.; Richards, L. J.; Zhang, J.; Joyner, A. L.; Tchieu, J.; Li, Y.; Shi, S.-H.

doi:10.64898/2025.12.27.696675

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bioRxiv · 10.64898/2025.12.27.696675

Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation

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Abstract

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. HIGHLIGHTSO_LINFIs affect human RGP temporal development coinciding with patient phenotypes. C_LIO_LINFI removal protracts RGP lineage progression and lifespan with excessive progeny output. C_LIO_LINFI overexpression accelerates RGP lineage progression with precocious progeny output. C_LIO_LINFIs regulate distinct temporal-specific targets underlying RGP lineage progression. C_LI

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Zhang, Q., Yuan, G., Albizzati, E., Yang, J., Zhao, Z., Yu, X., Chang, X., Lee, C. H., Du, H., Lao, Z., Krishnamurthy, A., Zhang, X., Lv, X., Tang, X., Hu, S., Chi, Y., Ma, J., Gronostajski, R. M., Richards, L. J., Zhang, J., Joyner, A. L., Tchieu, J., Li, Y., Shi, S.-H.. 2025-12-27. Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation. https://doi.org/10.64898/2025.12.27.696675

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