Migration of cerebellar neuronal precursors is stimulated by a synthetic peptide analogous to SDF-1/CXCL12 N-terminal

During the development of the nervous system, neural progenitor cells migrate from the germinal epithelia where they are born to their final destinations. The chemokine receptor CXCR4 plays a decisive role in physiological cell migration both in developmental processes and adult tissues. Studies have shown that SDF1/CXCL12 regulates migration of cerebellar granular neurons, chemoattracts microglia, and stimulates cytokine production and glutamate release by astrocytes. In the developing cerebellum the expression of SDF1/CXCL12 is higher in the external granular layer than in the internal granular layer, creating a gradient of this chemokine. It has been proposed that this gradient would prevent the granule cells to leave the external granular layer until the appropriate developmental timepoint. This suggested that early events in cerebellar granule cell morphogenesis, such as axon initiation, axon elongation, or migration of the cell body, might be severely perturbed in the absence of SDF1/CXCL12 signaling. Subsequently, it has been shown that CXCR4 null embryos also exhibit other phenotypes that reflect the abnormal migration of neuronal progenitors, including malformation of the dentate gyrus, lack of interneuron migration to the cortex, hypoplastic cortex and, most recently, malformation of the dorsal root ganglia. Mice deficient for the chemokine receptor CXCR4 show premature translocation of granule cell neuroblasts from their germinal zone into the nascent cerebellum. SDF1/CXCL12 is necessary for the normal development of the dentate gyrus, a forebrain structure crucial for learning and memory. To extend these observations, the activity of a synthetic peptide analogous to the N-terminus of SDF-1/CXCL12 on neuronal precursor migration and survival were examined in vitro. We first observed that migration of murine cerebellar neuronal precursors was stimulated by 3x10-7M of the SDF-1/CXCL12 analog as observed by real time in vitro assay. The peptide stimulated the percentage of migrating cells without affecting distance, duration or velocity of migration. On the other hand, the peptide was not able to promote neuronal precursors survival in the absence of KCl and growth factors. Taken together our results indicate that we have synthesized a peptide analog to SDF-1/CXCL12 that is able to induce chemotaxis and random migration of cells that express CXCR4, but it does not promote neuronal cell survival. Support: FAPESP, CNPq, FADA/UNIFESP, MCT/CNPq, DECIT/MS, Fundo Setorial de Biotecnologia (CT-BIOTECNOLOGIA).