Midkine and secondary neurulation

Midkine (MK) is a growth factor with documented neurotrophic activity for central nervous system neurons. It has also been shown to induce conversion of pluripotent mesenchymal P19 embryonic carcinoma cells into neuroepithelial derivatives. During the development of the chick embryonic neuraxis, two separate events occur. The anterior, greater portion of the neural tube, the primary neural tube, develops first from the neuroectoderm. The posterior section of the neural tube or the secondary neural tube forms next, from the cells of the tail bud, as tail bud cells undergo mesenchymal-neuroepithelial conversion. Disruptions in tail bud differentiation lead to defects of the secondary neural tube. In this study, antisense oligodeoxynucleotides (ODNs) were used to inhibit MK expression in order to determine if MK has a role in the mesenchymal-neuroepithelial conversion process. Chick embryos at the tail bud anlagen stage were treated with antisense ODNs to MK mRNA by sub-blastodermal injection and reincubated for 24 or 48 hr. The antisense ODN treatment resulted in a significant increase in the incidence of secondary neural tube defects, compared to control treatments with the saline vehicle only, sense ODNs, scrambled antisense ODNs, or non-sense ODNs. The loss of MK mRNA in the antisense ODN-treated embryos was confirmed by in situ hybridization. The results therefore suggest a role for MK in the mesenchymal-neuroepithelial conversion of tail bud mesenchyme into the secondary neural tube.