Maeda N, Noda M
Division of Molecular Neurobiology, National Institute for Basic Biology, and Department of Molecular Biomechanics, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan.
J Cell Biol. 1998 Jul 13;142(1):203-16. doi: 10.1083/jcb.142.1.203.
Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) is a specific ligand of protein tyrosine phosphatase zeta (PTPzeta)/receptor-like protein tyrosine phosphatase beta (RPTPbeta) expressed in the brain as a chondroitin sulfate proteoglycan. Pleiotrophin and PTPzeta isoforms are localized along the radial glial fibers, a scaffold for neuronal migration, suggesting that these molecules are involved in migratory processes of neurons during brain development. In this study, we examined the roles of pleiotrophin-PTPzeta interaction in the neuronal migration using cell migration assay systems with glass fibers and Boyden chambers. Pleiotrophin and poly-L-lysine coated on the substratums stimulated cell migration of cortical neurons, while laminin, fibronectin, and tenascin exerted almost no effect. Pleiotrophin-induced and poly-L-lysine-induced neuronal migrations showed significant differences in sensitivity to various molecules and reagents. Polyclonal antibodies against the extracellular domain of PTPzeta, PTPzeta-S, an extracellular secreted form of PTPzeta, and sodium vanadate, a protein tyrosine phosphatase inhibitor, added into the culture medium strongly suppressed specifically the pleiotrophin-induced neuronal migration. Furthermore, chondroitin sulfate C but not chondroitin sulfate A inhibited pleiotrophin-induced neuronal migration, in good accordance with our previous findings that chondroitin sulfate constitutes a part of the pleiotrophin-binding site of PTPzeta, and PTPzeta-pleiotrophin binding is inhibited by chondroitin sulfate C but not by chondroitin sulfate A. Immunocytochemical analysis indicated that the transmembrane forms of PTPzeta are expressed on the migrating neurons especially at the lamellipodia along the leading processes. These results suggest that PTPzeta is involved in the neuronal migration as a neuronal receptor of pleiotrophin distributed along radial glial fibers.
多效生长因子/肝素结合生长相关分子（HB - GAM）是蛋白酪氨酸磷酸酶ζ（PTPζ）/受体样蛋白酪氨酸磷酸酶β（RPTPβ）的特异性配体，在脑中作为硫酸软骨素蛋白聚糖表达。多效生长因子和PTPζ同工型定位于放射状胶质纤维上，这是神经元迁移的支架，表明这些分子参与脑发育过程中神经元的迁移过程。在本研究中，我们使用玻璃纤维和博伊登小室的细胞迁移测定系统，研究了多效生长因子 - PTPζ相互作用在神经元迁移中的作用。包被在基质上的多效生长因子和聚 - L - 赖氨酸刺激皮质神经元的细胞迁移，而层粘连蛋白、纤连蛋白和腱生蛋白几乎没有作用。多效生长因子诱导的和聚 - L - 赖氨酸诱导的神经元迁移在对各种分子和试剂的敏感性上显示出显著差异。加入培养基中的针对PTPζ细胞外结构域的多克隆抗体、PTPζ - S（PTPζ的一种细胞外分泌形式）以及蛋白酪氨酸磷酸酶抑制剂钒酸钠，强烈且特异性地抑制了多效生长因子诱导的神经元迁移。此外，硫酸软骨素C而非硫酸软骨素A抑制了多效生长因子诱导的神经元迁移，这与我们之前的发现一致，即硫酸软骨素构成PTPζ多效生长因子结合位点的一部分，并且硫酸软骨素C而非硫酸软骨素A抑制PTPζ - 多效生长因子的结合。免疫细胞化学分析表明，PTPζ的跨膜形式在迁移的神经元上表达，尤其是在沿着前沿突起的片状伪足处。这些结果表明，PTPζ作为沿放射状胶质纤维分布的多效生长因子的神经元受体参与神经元迁移。
