In Vivo Detection of Sonic Hedgehog (Shh) Signaling During Postnatal Myelination and After Acute and Chronic Demyelination
Abstract
Multiple sclerosis is a demyelinating disease characterized by progressive disability from axonal damage and inefficient remyelination in chronic disease stages. Our studies tested Sonic hedgehog (Shh) as a therapeutic target to promote remyelination. Shh modulates embryonic and postnatal myelination and regulates neural stem cells (NSC) in adults. We used inducible genetic fate labeling to detect in vivo activation of canonical Shh signaling. ShhCreERT2 or Gli1CreERT2 mice were crossed to reporter mice to fate label cells actively transcribing Shh or Gli1, an effective readout of canonical Shh signaling. Tamoxifen administration on postnatal days 6-9 (P6-9) in ShhCreERT2 crosses identified neurons as the major source of Shh synthesis. In Gli1CreERT2 crosses, tamoxifen from P6-9 fate-labeled cells that populated the corpus callosum (CC) and expressed oligodendrocyte lineage cells markers for progenitors and mature oligodendrocytes. Gli1 fate-labeled cells were also found in the ventricular-subventricular zone, a germinal site for NSCs. Gli1 fate-labeled cells that survived to adulthood proliferated and differentiated into mature oligodendrocytes in response to acute and chronic demyelination with cuprizone. Delaying tamoxifen administration until P14-17 revealed a drastic reduction of Shh and Gli1 expressing cells. Interestingly, cells fate-labeled for Gli1 from P14-17 or in adulthood rarely populated the healthy CC. Tamoxifen was next administered to adult ShhCreERT2 and Gli1CreERT2 mice during the course of demyelination and remyelination. Gli1 fate-labeled astrocytes began to localize within the CC after chronic demyelination but not after acute demyelination. Surprisingly, Shh expression was not detected in activated microglia, reactive astrocytes, or other CC cells within acute or chronic lesions.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 16, 2018
- Accession Number
- AD1132093
Entities
People
- Maria A. Sanchez
Organizations
- Uniformed Services University of the Health Sciences