We present evidence that the microtubuleassociated protein tau is present in oligodendrocytes (OLGs), the central nervous system cells that make myelin. By showing that tau is distributed in a pattern similar to that of myelin basic protein, our results suggest a possible involvement of tau in some aspect of myelination. Tau protein has been identified in OLGs in situ and in vitro. In interfascicular OLGs, tau localization, revealed by monoclonal antibody Tau-5, was confined to the cell somata. However, in cultured ovine OLGs with an exuberant network of processes, tau was detected in cell somata, cellular processes, and membrane expansions at the tips of these processes. Moreover, in such cultures, tau appeared localized adjacent to or coincident with myelin basic protein in membrane expansions along and at the ends of the cellular processes. The presence of tau mRNA was documented using fluorescence in situ hybridization. The distribution of the tau mRNA was similar to that of the tau protein.Western blot analysis of cultured OLGs showed the presence of many tau isoforms. Together, these results demonstrate that tau is a genuine oligodendrocyte protein and pave the way for determining its functional role in these cells.

Microtubule-associated protein 1B (MAP1B) is essential for neural development. Besides the abundant expression in neurons, MAP1B recently was found in myelinating oligodendroglia. Moreover, MAP1B deficiency causes delayed myelin development, suggesting the functional importance of MAP1B in oligodendroglia. However, molecular mechanisms that control MAP1B expression in oligodendroglia remain elusive. We report here that MAP1B mRNA is markedly upregulated in the oligodendroglia cell line CG4 upon induced differentiation, leading to elevated MAP1B protein production. A coordinated regulation of homeoprotein transcription factors was observed during CG4 cell differentiation, which recapitulates the regulation in neurons that promotes MAP1B transcription. Hence, transcriptional regulation of MAP1B appears to be a common mechanism in both neurons and oligodendroglia. In addition, we found posttranscriptional regulation of MAP1B mRNA by the selective RNA-binding protein QKI in oligodendroglia. The 3UTR of MAP1B mRNA interacts with QKI, and oligodendroglia-specific QKI-deficiency in the quakingviable mutant mice resulted in reduced MAP1B mRNA expression. Moreover, RNAi-mediated QKI-knockdown caused destabilization of the MAP1B mRNA in CG4 cells. Furthermore, forced expression of exogenous QKI was sufficient for promoting MAP1B expression. Because QKI is absent in neurons, QKI-dependent stabilization of MAP1B mRNA provides a novel mechanism for advancing MAP1B expression specifically in oligodendroglia during brain development. INTRODUCTIONMicrotubule-associated proteins (MAPs) control the dynamic organization of microtubule cytoskeleton, which in turn governs normal cell growth and development (Takemura et al., 1992;Hirokawa, 1994). Among these MAPs, MAP1B is predominantly expressed in the nervous system and is the earliest MAP detected in the embryonic brain (Tucker et al., 1989;Ma et al., 1997;Ohyu et al., 1997). Historically, MAP1B, which has been studied mainly in the developing neurons, plays essential roles in neurite outgrowth, axonal extension, and path finding (Gonzalez-Billault et al., 2001, 2002Bouquet et al., 2004). MAP1B expression is markedly upregulated during neurite outgrowth in various types of neurons (Gordon-Weeks and Fischer, 2000), and MAP1B knockout mice exhibit a range of abnormalities in axonal extension and path finding (Meixner et al., 2000;Gonzalez-Billault et al., 2001;Bouquet et al., 2004). More recent studies indicated that MAP1B expression is not restricted in neurons, but also is detected in oligodendrocytes and Schwann cells that produce myelin in the central and peripheral nervous system (CNS and PNS), respectively (Fischer et al., 1990;Ma et al., 1999). In particular, MAP1B expression is elevated in oligodendrocytes that initiate ensheathment of neuronal axons during normal brain development (Wu et al., 2001) as well as in Schwann cells during nerve regeneration (Ma et al., 1999).The functional importance of MAP1B in CNS myelination is further reinforced by the defects of myelin devel...

Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular transport, cognition, and aggregate regulation. Traditionally, neuroprotection exerted by histone deacetylase (HDAC) inhibitors (HDACi) has been attributed to the ability of this drug class to promote histone acetylation. However, HDAC6 in the healthy CNS functions via distinct mechanisms, due largely to its cytoplasmic localization. Indeed, in healthy neurons, cytoplasmic HDAC6 regulates the acetylation of a variety of non-histone proteins that are linked to separate functions, i.e., intracellular transport, neurotransmitter release, and aggregate formation. These three HDAC6 activities could work independently or in synergy. Of particular interest, HDAC6 targets the synaptic protein Bruchpilot and neurotransmitter release. In pathological conditions, HDAC6 becomes abundant in the nucleus, with deleterious consequences for transcription regulation and synapses. Thus, HDAC6 plays a leading role in neuronal health or dysfunction. Here, we review recent findings and novel conclusions on the role of HDAC6 in neurodegeneration. Selective studies with pan-HDACi are also included. We propose that an early alteration of HDAC6 undermines synaptic transmission, while altering transport and aggregation, eventually leading to neurodegeneration.

Oligodendrocytes and neurons derive from the same cell type but develop distinct morphologic and functional properties as they mature in vivo. Both cells express tau protein, a developmentally regulated protein in the central nervous system. The regulation of tau has been investigated extensively in neurons but not in oligodendrocytes, so we studied regulation of tau in oligodendrocytes in vivo. The amino-derived tau isoforms consist of isoforms with zero (A0), one (A1), or two (A2) inserts. We examined the developmental regulation of tau mRNA isoforms at the amino domain by comparing tau expression in oligodendrocytes (OLGs) isolated from 1- and 20-day-old rat brain and in age-matched cortex, which abounds in neurons. In the rat brain, myelination peaks at 20 days. By using semiquantitative RT-PCR, we found that OLGs and cortex from 1-day-old rat brain largely had amino-derived tau isoforms with no insert, whereas OLGs from 20-day-old rat brain had similar levels of amino-derived tau isoforms with no insert or with one insert. We also found that 20-day-old OLGs had twofold more tau mRNA levels than younger OLGs. In contrast to OLGs from 20-day-old rat brain, age-matched cortex had comparable levels of A0, A1, and A2 tau amino-derived isoforms. Further, younger and older OLGs had a reciprocal pattern of expression of both carboxy-derived tau mRNA isoforms with either three (3R) or four (4R) repeats. In contrast, younger and older cortex expressed either 3R or 4R tau. This study showed an upregulation of tau mRNA and cell-specific tau mRNA isoform expression in OLGs forming myelin.

The mechanisms underlying developmental myelination have therapeutic potential following CNS injury and degeneration. We report that transplanted central glial (