チロシンホスファターゼδのSIRPαリン酸化制御による皮質錐体細胞の樹状突起伸長

抄録

We previously reported that protein tyrosine phosphatase delta (PTPd), one of type IIa receptor type protein tyrosine phosphatases, mediates Sema3A-induced dendritic growth of cortical pyramidal neurons. However, its endogenous substrates involved in cortical dendritic arborization have been yet identified. Phosphotyrosine-proteome analysis of PTPd knockout brains revealed the hyperphosphorylation of Signal Regulatory Protein alpha (SIRPa) at Tyr501 (Y501) residue. Immunohistochemistry with anti-phospho-Y501 SIRPa antibody showed that olfactory epithelium, cortical II to V layers, thalamic nuclei and axon-bundles including corpus callosum, fimbria, and pyramidal tract were hyperphosphorylated in PTPd knockout brains. Knockdown of SIRPa by siRNA transfection or the overexpression of cytoplasmic deletion mutant of SIRPa suppressed Sema3A-induced growth cone collapse response of mouse dorsal root ganglion neurons. Primary culture of mouse cortical neurons revealed that Sema3A-stimulation induced the dephosphorylation of SIRPa in the dendritic growth cones of wild-type but not in those of PTPd knockouts. Overexpression of non-phosphorylated SIRPa mutant Y501F in cultured cortical neurons attenuated Sema3A-induced dendritic growth. In utero electroporation of SIRPa-Y501F to mouse brains showed that the apical dendrites of cortical layer II/III pyramidal neurons were disoriented. Similar irregular projection of cortical apical dendrites was also observed in PTPd knockout brains. These results suggest that PTPd may regulate the phosphorylation of SIRPa in cortical dendritic growth.