Regulation and differential expression of tau mRNA isoforms as oligodendrocytes mature in vivo: Implications for myelination

Abstract

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.

?IV tubulin is selectively expressed by oligodendrocytes in the central nervous system

“…Isotype-specific C-terminals interact differentially with some MAPs (Paschal et al, 1989;Cross et al, 1994), and isotype-related differences in MAP-promoted MT assembly have been reported (Banerjee et al, 1992;Lu and Luduena, 1994). Oligodendrocytes upregulate MAP-1B (Fischer et al, 1990;Vouyiouklis and Brophy, 1993), MAP-2c (Muller et al, 1997;Richter-Landsberg and Gorath, 1999), MAP-2e (also called MAP2þ13; Shafit-Zagardo et al, 1999, MAP-4 (Vouyiouklis and Brophy, 1995), and the four-repeat tau isoforms (Richter-Landsberg and Gorath, 1999;LoPresti, 2002) during myelination. Enrichment for b IV tubulin and these MAPs may promote formation of an MT network with stability and transport characteristics necessary for myelination.…”

Spatial and temporal expression of S100B in cells of oligodendrocyte lineage

“…Although direct evidence for specific S100B functions during OL differentiation is still missing, it is known that, during their maturation, OLs develop cytoplasmic extensions and flat membranous sheets that contain an extensive cytoskeletal network of microtubules (RichterLandsberg, 2001). OLs express the MT-associated proteins MAP2 and tau (LoPresti, 2002), whose phosphorylation by protein kinase II is inhibited in vitro in a calcium-dependent manner by S100B (Baudier and Cole, 1988). Therefore, we predict a role for S100B in regulating OL cell shape that is consistent with its documented association with microtubular structures in cultured oligodendrocytes (Richter-Landsberg and Heinrich, 1995;Sorci et al, 2000).…”

Tau in Oligodendrocytes Takes Neurons in Sickness and in Health

“…In contrast, missorting of tau causes reduced myelin and axonal degeneration (Figure 1). To understand which levels of tau regulation in OLGs can be targeted, several studies have established the importance of tau mRNA splicing and of tau posttranslational modifications [9,13,33,34,35]. These events are key to understand how tau can promote either CNS health or disease.…”

“…These events are key to understand how tau can promote either CNS health or disease. Tau mRNA splicing is highly regulated and, in a cell-specific pattern [13]. Contrary to the pattern of neuron regulation, which has a developmentally regulated shift in the tau mRNA form expressed in the young versus adult rodent CNS, tau regulation in OLGs is specific to these cells, with the persistent presence in the adult CNS of forms of tau mRNA splicing that are abundant in neonatal neurons.…”

“…In OLGs, tau plays a key role in myelination [11,12,13,14], and its malfunction causes myelin and movement disorders [15,16] (Figure 1). It is not surprising that OLG tau can be either beneficial or detrimental, as it regulates events within cellular processes that are essential for cellular process extension and myelin formation [12,13,14,17,18]. Areas of future research must seek to understand the molecular mechanisms by which OLG tau impacts the neurons, and how a deregulation of OLG tau might negatively impact the OLG-neuron unit.…”