Cortical Neural Stem Cell Lineage Progression Is Regulated by Extrinsic Signaling Molecule Sonic Hedgehog

Cell Rep. 2020 Mar 31;30(13):4490-4504.e4. doi: 10.1016/j.celrep.2020.03.027.


Neural stem cells (NSCs) in the prenatal neocortex progressively generate different subtypes of glutamatergic projection neurons. Following that, NSCs have a major switch in their progenitor properties and produce γ-aminobutyric acid (GABAergic) interneurons for the olfactory bulb (OB), cortical oligodendrocytes, and astrocytes. Herein, we provide evidence for the molecular mechanism that underlies this switch in the state of neocortical NSCs. We show that, at around E16.5, mouse neocortical NSCs start to generate GSX2-expressing (GSX2+) intermediate progenitor cells (IPCs). In vivo lineage-tracing study revealed that GSX2+ IPC population gives rise not only to OB interneurons but also to cortical oligodendrocytes and astrocytes, suggesting that they are a tri-potential population. We demonstrated that Sonic hedgehog signaling is both necessary and sufficient for the generation of GSX2+ IPCs by reducing GLI3R protein levels. Using single-cell RNA sequencing, we identify the transcriptional profile of GSX2+ IPCs and the process of the lineage switch of cortical NSCs.

Keywords: Gli3; Gsx2; Shh; cerebral cortex; neural stem cells; olfactory bulb interneurons; oligodendrocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Biomarkers / metabolism
  • Cell Lineage*
  • Embryo, Mammalian / metabolism
  • Hedgehog Proteins / metabolism*
  • Homeodomain Proteins / metabolism
  • Interneurons / cytology
  • Mice, Inbred C57BL
  • Neocortex / cytology*
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism*
  • Neurogenesis
  • Neuroglia / cytology
  • Neuroglia / metabolism
  • Olfactory Bulb / cytology
  • Oligodendroglia / metabolism
  • Pyramidal Cells / cytology
  • Pyramidal Cells / metabolism
  • Reproducibility of Results
  • Signal Transduction*
  • Zinc Finger Protein Gli3 / metabolism


  • Biomarkers
  • Gli3 protein, mouse
  • Gsh2 protein, mouse
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Zinc Finger Protein Gli3