Midkine (MK) is a 13-kDa heparin-binding growth/differentiation factor, and its interaction with heparan sulfate proteoglycan is important in promotion of neurite outgrowth. This study was performed to reveal the species of syndecans that interact with MK during embryogenesis of the central nervous system in the rat. Northern blot analysis and immunohistochemical staining using antibodies to syndecans showed that syndecan-1 was strongly expressed in the brain and spinal cord of the 10-day rat fetus, and the expression became weak as embryogenesis proceeded. On the other hand, syndecan-3 expression was stronger both in the brain and spinal cord in the later developmental period (day 14-16 of gestation). No significant expression of ryudocan (syndecan-4) was detected in fetal brains by Northern blot analysis. Syndecan-3 isolated from 16-day rat fetus bound to MK strongly, as did syndecan-1 isolated from 10-day rat fetus. Thus, both syndecan-1 and syndecan-3 were considered to be involved in interaction with MK during construction of the central nervous system; syndecan-1 is expected to play important roles in the earlier periods, and syndecan-3 in the later periods.