Abstract Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by aberrant immune responses. The current immune modulatory therapies are unable to protect and repair the brain damage caused by the immune attack. One of the therapeutic targets for MS is the sphingosine-1-phosphate (S1P) pathways, which signals via sphingosine-1-phosphate receptors 1-5 (S1P1-5), in the CNS and immune cells. In light of the potential neuro-protective properties of S1P signaling, we utilized the S1P1-GFP (Green fluorescent protein) reporter mice in the cuprizone-induced-demyelination model, to investigate the in vivo S1P- S1P1 signaling in the CNS. We observed S1P1 signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. Additionally, oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC) expressed S1P1 signaling during remyelination. We did not observe S1P1 signaling in neurons and astrocytes in the cuprizone model. This approach was unable to determine S1P1-GFP signaling in the myeloid cells because of their aberrant GFP expression in GFP reporter mice. Significant S1P1 signaling was observed in lymphocytes during demyelination and inflammation. Our findings reveal β-arrestin dependent S1P1 signaling in oligodendrocyte lineage cells, indicating a role of S1P1 signaling during remyelination.