Neu Differentiation Factor Regulates Tau Protein and mRNA in Cultured Neonatal Oligodendrocytes PATRIZIA LOPRESTI, 1 * NANCY A. MUMA, 2 AND GEORGE H. DE VRIES 3,4 1 Department of Pathology, Loyola University Medical Center, Maywood, Illinois 2 Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 3 Research Service Hines VA Hospital, Hines, Hines, Illinois 4 Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Medical Center, Maywood, Illinois KEY WORDS neuregulins; cytoskeleton; oligodendrocyte-axon interaction; myelina- tion; growth factors ABSTRACT Axonal signals activate myelinogenesis via regulation of the extent to which oligodendrocyte (OLG) processes wrap around the axon. The cytoskeleton in OLG processes is actively involved in myelination and is a putative target for axonal regula- tion of myelination. The axon-associated neuregulins may regulate the cytoskeleton extensions in OLG processes. Here, we report that the neuregulin neu differentiation factor (NDF) increases the expression of tau mRNA and tau protein in OLGs. Treatment of neonatal OLGs with -NDF or -NDF resulted in dramatic increases in the length of OLG processes, which appeared either as singular unbranched extensions or as a network of extensively branched processes. By immunoblot analysis with tau-1 mAb, which recognizes the dephosphorylated form of the tau proteins, neonatal OLGs treated with -NDF or -NDF, had an increase in tau protein levels. The increase of tau levels in -NDF–treated cells is much greater than the twofold increase present in -NDF– treated cells. By immunoblot analysis with the phosphorylation-insensitive tau-5 mAb, -NDF–treated cells had a twofold increase in tau. Immunoblot analysis suggest that -NDF and -NDF promote a twofold increase in the tau protein levels in OLG, with the -factor also promoting a tau dephosphorylation. Using promoters spanning the amino- terminal region of tau, we found that OLGs treated with -NDF or -NDF contained approximately twofold more tau mRNA than untreated cells. However, there was no qualitative difference between control and NDF-treated cells in the pattern of tau mRNA isoforms expressed. A model is proposed in which the axonal NDF-induced regulation of tau expression in OLGs may be part of the mechanism by which the axon regulates myelination. GLIA 35:147–155, 2001. © 2001 Wiley-Liss, Inc. INTRODUCTION Myelination begins when oligodendrocytes (OLGs) encounter axons. Although OLGs form myelin mem- brane-like sheaths in vitro in the absence of neurons, the level of myelin-specific genes increases about four- fold when neurons are added to the OLG cultures (Macklin et al., 1986). This cell-cell contact activates a cascade of biochemical events, which trigger the mor- phological and functional properties of myelin-forming OLGs. Myelination consists of a series of complex events, which include extensive biogenesis of the OLG membrane surrounding the axon, the upregulation of myelin-specific gene expression, and the translocation of myelin basic protein (MBP) mRNA from the OLG soma to the tips of processes (Colman et al., 1986; *Correspondence to: Patrizia LoPresti, Department of Neurobiology and Phys- iology, Northwestern University, Hogan Hall, 2153 N. Campus Drive, Evanston, IL 60208. E-mail: p-lopresti@northwestern.edu Received 5 January 2000; Accepted 1 June 2001 Published online 9 July 2001 GLIA 35:147–155 (2001) © 2001 Wiley-Liss, Inc.