Postnatal Sonic Hedgehog (Shh) Responsive Cells Give Rise to Oligodendrocyte Lineage Cells During Myelination and in Adulthood Contribute to Remyelination

Exp Neurol. 2018 Jan;299(Pt A):122-136. doi: 10.1016/j.expneurol.2017.10.010. Epub 2017 Oct 16.

Abstract

Sonic hedgehog (Shh) regulates a wave of oligodendrocyte production for extensive myelination during postnatal development. During this postnatal period of oligodendrogenesis, we fate-labeled cells exhibiting active Shh signaling to examine their contribution to the regenerative response during remyelination. Bitransgenic mouse lines were generated for induced genetic fate-labeling of cells actively transcribing Shh or Gli1. Gli1 transcription is an effective readout for canonical Shh signaling. ShhCreERT2 mice and Gli1CreERT2 mice were crossed to either R26tdTomato mice to label cells with red fluorescence, or, R26IAP mice to label membranes with alkaline phosphatase. When tamoxifen (TMX) was given on postnatal days 6-9 (P6-9), Shh ligand synthesis was prevalent in neurons of ShhCreERT2; R26tdTomato mice and ShhCreERT2;R26IAP mice. In Gli1CreERT2 crosses, TMX from P6-9 detected Gli1 transcription in cells that populated the corpus callosum (CC) during postnatal myelination. Delaying TMX to P14-17, after the peak of oligodendrogenesis, significantly reduced labeling of Shh synthesizing neurons and Gli1 expressing cells in the CC. Importantly, Gli1CreERT2;R26tdTomato mice given TMX from P6-9 showed Gli1 fate-labeled cells in the adult (P56) CC, including cycling progenitor cells identified by EdU incorporation and NG2 immunolabeling. Furthermore, after cuprizone demyelination of the adult CC, Gli1 fate-labeled cells incorporated EdU and were immunolabeled by NG2 early during remyelination while forming myelin-like membranes after longer periods for remyelination to progress. These studies reveal a postnatal cell population with transient Shh signaling that contributes to oligodendrogenesis during CC myelination, and gives rise to cells that continue to proliferate in adulthood and contribute to CC remyelination.

Keywords: Cuprizone; Demyelination; Genetic fate labeling; Gli1; Myelination; Oligodendrocyte lineage; Oligodendrocyte progenitor; Oligodendrogenesis; Remyelination; Sonic hedgehog.

MeSH terms

  • Alkaline Phosphatase / metabolism
  • Animals
  • Cell Lineage / genetics*
  • Cell Membrane / metabolism
  • Cell Proliferation / drug effects
  • Chelating Agents
  • Corpus Callosum / metabolism
  • Corpus Callosum / pathology
  • Cuprizone
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / genetics
  • Demyelinating Diseases / prevention & control
  • Female
  • Hedgehog Proteins / genetics*
  • Male
  • Mice
  • Myelin Sheath / drug effects
  • Myelin Sheath / pathology*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Oligodendroglia / drug effects*
  • Zinc Finger Protein GLI1 / biosynthesis
  • Zinc Finger Protein GLI1 / genetics

Substances

  • Chelating Agents
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Shh protein, mouse
  • Zinc Finger Protein GLI1
  • Cuprizone
  • Alkaline Phosphatase