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.
Funding Information
  • STI2030-Major Projects (2021ZD0202300)
  • National Natural Science Foundation of China (32021002)
  • Beijing Outstanding Young Scientist Program (BJJWZYJH01201910003012)
  • Beijing Municipal Science & Technology Commission (Z211100003321001)
  • Beijing Municipal Science & Technology Commission (Z221100003422011)
  • New Cornerstone Investigator Program
  • Tsinghua University Initiative Scientific Research Program
  • the NIH (R01DA024681)
  • the NIH (P30CA008748)
  • the Tri-SCI (2019-022)
  • The National Key R&D Program of China (2024YFA09196)
  • The National Key R&D Program of China (2024YFA09173)
  • The National Key R&D Program of China (2019YFA0904400)
  • The National Key R&D Program of China (2019YFA0906700)
  • Beijing Natural Science Foundation (Z210010)
  • The National Natural Science Foundation of China (32171448)
  • Tsinghua University Initiative Scientific Research Program (2024Z11DSZ001)
  • Tsinghua University Initiative Scientific Research Program (2022Z11QYJ032)
  • Tsinghua University Initiative Scientific Research Program (2021Z11JCQ020)
  • NIH Pioneer Award (DP1OD031273)

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