In vivo contribution of nestin- and GLAST-lineage cells to adult hippocampal neurogenesis

Hippocampus. 2013 Aug;23(8):708-19. doi: 10.1002/hipo.22130. Epub 2013 May 17.

Abstract

Radial glia-like cells (RGCs) are the hypothesized source of adult hippocampal neurogenesis. However, the current model of hippocampal neurogenesis does not fully incorporate the in vivo heterogeneity of RGCs. In order to better understand the contribution of different RGC subtypes to adult hippocampal neurogenesis, we employed widely used transgenic lines (Nestin-CreER(T2) and GLAST::CreER(T2) mice) to explore how RGCs contribute to neurogenesis under basal conditions and after stimulation and depletion of neural progenitor cells. We first used these inducible fate-tracking transgenic lines to define the similarities and differences in the contribution of nestin- and GLAST-lineage cells to basal long-term hippocampal neurogenesis. We then explored the ability of nestin- and GLAST-lineage RGCs to contribute to neurogenesis after experimental manipulations that either ablate neurogenesis (i.c.v. application of the anti-mitotic AraC, cytosine-β-D-arabinofuranoside) or stimulate neurogenesis (wheel running). Interestingly, in both ablation and stimulation experiments, labeled RGCs in GLAST::CreER(T2) mice appear to contribute to neurogenesis, whereas RGCs in Nestin-CreER(T2) mice do not. Finally, using NestinGFP reporter mice, we expanded on previous research by showing that not all RGCs in the adult dentate gyrus subgranular zone express nestin, and therefore RGCs are antigenically heterogeneous. These findings are important for the field, as they allow appropriately conservative interpretation of existing and future data that emerge from these inducible transgenic lines. These findings also raise important questions about the differences between transgenic driver lines, the heterogeneity of RGCs, and the potential differences in progenitor cell behavior between transgenic lines. As these findings highlight the possible differences in the contribution of cells to long-term neurogenesis in vivo, they indicate that the current models of hippocampal neurogenesis should be modified to include RGC lineage heterogeneity.

Keywords: Cre recombinase; dentate gyrus; genetic fate tracking; radial glial cell; subgranular zone.

Publication types

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

MeSH terms

  • Animals
  • Cell Lineage / physiology*
  • Excitatory Amino Acid Transporter 1 / genetics
  • Excitatory Amino Acid Transporter 1 / metabolism*
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins / metabolism
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / cytology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Motor Activity / physiology
  • Nerve Tissue Proteins / metabolism
  • Nestin / genetics
  • Nestin / metabolism*
  • Neurogenesis / physiology*
  • Neuroglia / physiology
  • Neurons / physiology
  • Neuropeptides / metabolism
  • Organ Culture Techniques
  • SOXB1 Transcription Factors / metabolism
  • Stem Cells / physiology

Substances

  • Excitatory Amino Acid Transporter 1
  • Fabp7 protein, mouse
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • Luminescent Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Neuropeptides
  • SOXB1 Transcription Factors
  • Slc1a3 protein, mouse
  • Sox2 protein, mouse
  • doublecortin protein