QKI Binds MAP1B mRNA and Enhances MAP1B Expression during Oligodendrocyte Development

Abstract

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...

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

“…It has been found to regulate multiple posttranscriptional processes, including premRNA splicing, mRNA localization, mRNA stability, and protein translation (43)(44)(45)(46)(47)(48)(49)(50). There are three major isoforms of QKI due to AS, QKI-5, QKI-6, and QKI-7 (51,52).…”

Rescuing qkvDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

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