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The Microtubule-Associated Protein Doublecortin-Like Regulates the Transport of the Glucocorticoid Receptor in Neuronal Progenitor Cells

Leiden/Amsterdam Center for Drug Research (C.P.F., S.A., C.F.W.W., T.G.S., T.F.D., R.d.K., E.V.), Medical Pharmacology Department, and Institute for Biology (M.J.M.S.), Clusius Laboratory, Leiden University, 2300 RA Leiden, The Netherlands; and Department of Cellular Animal Physiology (W.J.J.M.S.), Radboud University Nijmegen, 6500HP Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Erno Vreugdenhil, Leiden/Amsterdam Center for Drug Research/Medical Pharmacology Department, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: vreugden{at}lacdr.leidenuniv.nl.

In neuronal cells, activated glucocorticoid receptor (GR) translocates to the nucleus guided by the cytoskeleton. However, the detailed mechanisms underlying GR translocation remain unclear. Using gain and loss of function studies, we report here for the first time that the microtubule-associated protein doublecortin-like (DCL) controls GR translocation to the nucleus. DCL overexpression in COS-1 cells, neuroblastoma cells, and rat hippocampus organotypic slice cultures impaired GR translocation and decreased GR-dependent transcriptional activity, measured by a specific reporter gene assay, in COS-1 cells. Moreover, DCL and GR directly interact on microtubule bundles formed by DCL overexpression. A C-terminal truncated DCL with conserved microtubule-bundling activity did not influence GR translocation. In N1E-115 mouse neuroblastoma cells and neuronal progenitor cells in rat hippocampus organotypic slice cultures, laser-scanning confocal microscopy showed colabeling of endogenously expressed DCL and GR. In these systems, RNA-interference-mediated DCL knockdown hampered GR translocation. Thus, we conclude that DCL expression is tightly regulated to adequately control GR transport. Because DCL is primarily expressed in neuronal progenitor cells, our results introduce this microtubule-associated protein as a new modulator of GR signaling in this cell type and suggest the existence of cell-specific mechanisms regulating GR translocation to the nucleus.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Ligands:   Dexamethasone  |  Mifepristone

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