TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons

J Cell Mol Med. 2014 Jul;18(7):1444-59. doi: 10.1111/jcmm.12298. Epub 2014 Apr 30.

Abstract

Members of the transforming growth factor (TGF)-β family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF-β signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-β1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-β1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-β1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-β1 signalling in adult NPCs. The results demonstrate that TGF-β1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF-β1 in ageing and neurodegenerative diseases, TGF-β1 signalling presents a molecular target for future interventions in such conditions.

Keywords: Smad2; TGF-β1; cell cycle; differentiation; doublecortin; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Blotting, Western
  • Cell Differentiation*
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence
  • Electrophysiology
  • Female
  • Gene Expression Profiling
  • Hippocampus / cytology*
  • Hippocampus / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurogenesis / physiology*
  • Neurons / cytology*
  • Neurons / metabolism
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Inbred F344
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cell Niche*
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Biomarkers
  • RNA, Messenger
  • Transforming Growth Factor beta