In this study, we identify Sip1 as a common downstream target gene of Olig1 and Olig2. Overexpression or upregulation of Olig1 and Olig2 can activate Sip1 expression. Sip1 appears to bridge Olig Epacadostat supplier activities to balance the signaling pathways mediated by BMP/Smad and Wnt/β-catenin to control the timing of oligodendrocyte myelination. Our findings point to Sip1 as a master regulator that coordinates opposing signaling pathways to promote myelination and a nexus that connects extracellular signaling pathways to intracellular transcriptional programs for myelination in the CNS. The severe

myelination defect but preservation of OPCs in the CNS of Sip1 mutants suggests that Sip1 is a key regulator for the transition from immature to mature myelinating oligodendrocytes. Sip1 is robustly upregulated during OPC differentiation in vitro and in the postnatal CNS, consistent with the requirement for Sip1 in oligodendrocyte maturation. However, low levels of Sip1 in OPCs may

still regulate early steps of differentiation [e.g., by targeting negative regulatory genes Id2 and Hes1 in OPCs ( Figure 5)], which may in turn lead to more Sip1 accumulation in a positive feedback loop. Interaction of Sip1 with Smad1/Smad4/p300 complexes was found here to block BMP-Smad-activated expression of differentiation inhibitors, leading to derepression of myelin gene expression. In addition to Smad1, we expect similar outcome of Sip1 action on the activity of other closely related Smads (i.e., the other BMP-Smads, Smad5 and Smad8) by blocking the activity of LY294002 cell line almost p-Smads. In addition to interacting physically with p-Smads, Sip1 also antagonizes BMP signaling by activating at the transcriptional level an I-Smad,

Smad7, which in turn downregulates BMP receptor signaling. Recently, Sip1 was also found to inhibit expression of BMP ligands, like the BMP4 gene ( van Grunsven et al., 2007). Given that inhibition of BMP signaling (e.g., by ablating BMPR1a or by adding BMP antagonists) was shown to increase the number of mature oligodendrocytes and promote remyelination ( Sabo et al., 2011 and Samanta et al., 2007), the findings from our present studies and others suggest that Sip1 inhibits the BMP signaling pathway at multiple levels including the BMP ligand, its receptor, and its intracellular effectors to promote oligodendrocyte myelination. The modulation of various differentiation regulators by Sip1 appears to be stage-dependent. For instance, Sip1 binds the Smad7 promoter when OPCs begin to differentiate, while being recruited to Id2 and Hes1 promoters in OPCs and the Id4 promoter in differentiating oligodendrocytes, respectively, suggesting that stage-specific cofactors may direct the binding of Sip1 to different targets to modulate their expression.