The Role of Nde1 Phosphorylation in Interkinetic Nuclear Migration and Schizophrenia

Abstract

AbstractNde1 is a cytoplasmic dynein regulatory protein with important roles in vertebrate brain development. One noteworthy function is in the nuclear oscillatory behavior in neural progenitor cells, the control and mechanism of which remain poorly understood. Nde1 contains multiple phosphorylation sites for the cell cycle-dependent protein kinase CDK1, though the function of these sites is not well understood. To test their role in brain development we expressed phosphorylation-state mutant forms of Nde1 in embryonic rat brains usingin uteroelectroporation. We find that Nde1 T215 and T243 phosphomutants block apical interkinetic nuclear migration (INM) and, consequently, mitosis in radial glial progenitor cells. Another Nde1 phosphomutant at T246 also interfered with mitotic entry without affecting INM, suggesting a more direct role for Nde1 T246 in mitotic regulation. We also found that the Nde1 S214F mutation, which is associated with schizophrenia, inhibits CDK5 phosphorylation at an adjacent residue which causes alterations in neuronal lamination. These results together identify important new roles for Nde1 phosphorylation in neocortical development and disease and represent the first evidence for Nde1 phosphorylation roles in INM, neuronal lamination, and schizophrenia.Significance StatementThe results presented in this study show the importance of Nde1 phosphoregulation during successive stages of neocortical development. Nde1 dysregulation may, in turn, have important consequences in human psychiatric disorders, such as schizophrenia, as well. We observed clear and potent effects of specific Nde1 phosphomutants in the control of INM and neural development. Our results provide strong support for new insight into the little-understood mechanism for triggering RGP mitotic entry. In the course of these studies, we obtained clear evidence for a novel post-mitotic role for Nde1 phosphorylation in schizophrenia.