Y-P30 is a polypeptide produced by peripheral blood mononuclear cells of the maternal immune system during pregnancy. The peptide passes the blood-placenta barrier and accumulates in neurons of the developing infant brain, where it enhances survival of thalamic neurons and displays neuritogenic activities. In this study, we identify pleiotrophin (PTN) and syndecan-2 and -3 as direct binding partners of Y-P30. PTN is known to promote neurite outgrowth of thalamic neurons due to its association with the proteoglycan syndecan-3. Via spontaneous oligomerization Y-P30 can capture large macromolecular complexes containing PTN and potentially syndecans. Accordingly, the neuritogenic activity of Y-P30 in thalamic primary cultures requires the presence of PTN in the media and binding to syndecans. Thus, we propose that the neurite outgrowth promoting actions of Y-P30 during brain development are essentially based on its association with the PTN/syndecan signaling complex. This identifies a new mechanism of communication between the nervous and the immune system that might directly affect the wiring of the brain during development.