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Dual-Mode Modulation of Smad Signaling by Smad-Interacting Protein Sip1 Is Required for Myelination in the Central Nervous System

Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Neuron (Impact Factor: 15.98). 02/2012; 73(4):713-28. DOI: 10.1016/j.neuron.2011.12.021
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ABSTRACT Myelination by oligodendrocytes in the central nervous system (CNS) is essential for proper brain function, yet the molecular determinants that control this process remain poorly understood. The basic helix-loop-helix transcription factors Olig1 and Olig2 promote myelination, whereas bone morphogenetic protein (BMP) and Wnt/β-catenin signaling inhibit myelination. Here we show that these opposing regulators of myelination are functionally linked by the Olig1/2 common target Smad-interacting protein-1 (Sip1). We demonstrate that Sip1 is an essential modulator of CNS myelination. Sip1 represses differentiation inhibitory signals by antagonizing BMP receptor-activated Smad activity while activating crucial oligodendrocyte-promoting factors. Importantly, a key Sip1-activated target, Smad7, is required for oligodendrocyte differentiation and partially rescues differentiation defects caused by Sip1 loss. Smad7 promotes myelination by blocking the BMP- and β-catenin-negative regulatory pathways. Thus, our findings reveal that Sip1-mediated antagonism of inhibitory signaling is critical for promoting CNS myelination and point to new mediators for myelin repair.

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Available from: Eve Seuntjens, Aug 13, 2015
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    • "Briefly, OLIG1 regulates the expression of several genes involved in oligodendroglial maturation, including MBP, myelin oligodendrocytic glycoprotein, myelin proteolipid protein, and zinc finger protein 488 (Arnett et al., 2004; Xin et al., 2005; Wang et al., 2006; Guo et al., 2010). Additionally, OLIG2 has been found to play several critical roles in oligodendrocyte differentiation including enhancing the expression of Sox10 and Sip 1, proteins that enhance oligodendrogial activity and maturation of NG2-OPCs (Wang et al., 2006; Kuspert et al., 2011; Weng et al., 2012; Yu et al., 2013). However, OLIG2 also has been identified as a transcription repressor for several targets and consequently has been implicated in human glioma (Lee et al., 2005; Ligon et al., 2007; Mehta et al., 2011). "
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    • "Briefly, OLIG1 regulates the expression of several genes involved in oligodendroglial maturation, including MBP, myelin oligodendrocytic glycoprotein, myelin proteolipid protein, and zinc finger protein 488 (Arnett et al., 2004; Xin et al., 2005; Wang et al., 2006; Guo et al., 2010). Additionally, OLIG2 has been found to play several critical roles in oligodendrocyte differentiation including enhancing the expression of Sox10 and Sip 1, proteins that enhance oligodendrogial activity and maturation of NG2-OPCs (Wang et al., 2006; Kuspert et al., 2011; Weng et al., 2012; Yu et al., 2013). However, OLIG2 also has been identified as a transcription repressor for several targets and consequently has been implicated in human glioma (Lee et al., 2005; Ligon et al., 2007; Mehta et al., 2011). "
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    • "pression ( Bilican et al . , 2008 ) . A recent paper has identified Sip1 as an important regulator of oligodendrocyte differentiation and myelination . Sip1 represses BMP - Smad signalling , via a dual mechanism involving direct antagonism of Smad 1 / 5 / 8 and induction of Smad7 expression , to promote oligodendrocyte differentiation in the CNS ( Weng et al . , 2012 ) . Cheng et al . ( 2007 ) propose that the blocking of BMP - Smad signalling combined with olig1 / 2 overexpression could potentially enhance endogenous remyelination in CNS demyelination disorders . In support of this suggestion , local increases in BMPs at the site of demyelination upregulates gliosis , with these astrocytes display "
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