Commitment of developing Schwann cells to form myelin follows arrest of the cell cycle, increased expression of myelin-related proteins and morphological changes that initiate axon ensheathment. Autocrine/paracrine signalling between Schwann cells is partly responsible for maintaining viability (Meier et al. 1999), suppressing the cell cycle and initiating cell differentiation (Rushton et al. 1999). There is evidence that separate signal pathways mediate each of these processes.

Cyclic AMP is a potent intracellular signal leading to Schwann cell differentiation at the point of commitment. The edg-3 receptor for sphingosine 1-phosphate (SPP) is a prominent protein undergoing upregulation in response to cyclic AMP elevation (Bermingham et al. 2001). There is also evidence that the related edg receptor ligand lysophosphatidic acid (LPA) regulates Schwann cell development (Weiner et al. 2001). We have therefore investigated possible roles for SPP and LPA in the induction of differentiation using the rat Schwann cell strain, SCL4.1/F7. SPP but not LPA (both 0.1-1 µM), initiated transient release of free calcium, detected by fluo-4 multiwell fluorimetric imaging, in SCL4.1/F7 cells (n = 8). Responses to SPP were followed, within 1-3 h, by change of cells to a broad/flattened morphology (n = 5). This was similar to that seen during differentiation induced by paracrine factors released into the culture medium by SCL4.1/F7 cells, and was accompanied by translocation of actin filaments to the cell perimeter. LPA induced reorganization of actin filaments into parallel arrays atypical of normal cell differentiation. SPP and LPA (50 nM to 2 µM) both induced a small (20 %) dose-independent suppression of DNA synthesis (n = 18). A sphingolipid which co-migrates with SPP has been detected in SCL4.1/F7-conditioned medium using the sphingolipid-specific HPLC method of Ruwisch et al. (2001).

edg3 and edg5 receptors for SPP were both expressed during postnatal development in rat sciatic nerve and were localized to the internode of the nerve, and to SCL4.1/F7 cells ensheathing axons in co-culture with embryonic rat sensory ganglion neurons from humanely killed animals.

The results are consistent with the possibility that independent signals exist for the growth-arrest and differentiation of Schwann cells, and that SPP could promote differentiation through one or more of receptors of the edg superfamily.