Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging

Nat Neurosci. 2021 Feb;24(2):225-233. doi: 10.1038/s41593-020-00759-4. Epub 2020 Dec 21.


Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We used two-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI family zinc finger 1 (Gli1) or achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Lineage
  • Female
  • Gene Expression Profiling
  • Hippocampus / cytology
  • Hippocampus / growth & development*
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics
  • Intravital Microscopy
  • Male
  • Metallothionein 3
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence, Multiphoton
  • Nerve Regeneration
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Neural Stem Cells / physiology*
  • Single-Cell Analysis
  • Zinc Finger Protein GLI1 / biosynthesis
  • Zinc Finger Protein GLI1 / genetics


  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Gli1 protein, mouse
  • Hod protein, mouse
  • Homeodomain Proteins
  • Metallothionein 3
  • Nerve Tissue Proteins
  • Zinc Finger Protein GLI1