, 2009 and Ye et al., 2009).

Finally, Notch signaling activation by its downstream effectors (e.g., Hes1 and Hes5) was shown to inhibit the transition of OPCs to mature oligodendrocytes Dabrafenib mw and remyelination (Wang et al., 1998, Wu et al., 2003 and Zhang et al., 2009). As a potential mechanism to counter extrinsic suppressive signaling, a series of cell intrinsic factors, such as the basic helix-loop-helix transcription factors Olig1 and Olig2, have been identified to positively regulate differentiation of oligodendrocytes (Emery et al., 2009, He et al., 2007, Howng et al., 2010, Li et al., 2009, Wegner, 2008 and Ye et al., 2009). Olig2 directs early OPC specification and differentiation (Lu et al., 2002, Yue et al., 2006 and Zhou and Anderson, click here 2002); similarly, Olig1, whose expression is elevated during OPC differentiation, promotes oligodendrocyte maturation and is required for repair of demyelinated lesions (Arnett et al., 2004, Li et al., 2007 and Xin et al., 2005). This suggests that Olig1 and Olig2 have an overlapping function in regulating

myelination in the CNS. However, the underlying mechanisms that balance and coordinate extrinsic with intrinsic inhibitory cues to drive oligodendrocyte myelination are not fully understood. We hypothesized that the downstream effectors regulated by both Olig1 and Olig2 may function to coordinate the inhibitory pathways to promote myelination. By performing whole-genome chromatin immunoprecipitation (ChIP) sequencing Cytidine deaminase and gene profiling analysis, we identified a common target gene of Olig1 and Olig2 encoding

Smad-interacting protein-1 (Sip1; also named zinc finger homeobox protein 1b [Zfhx1b] or Zeb2). Our present studies reveal a critical role of the transcription factor Sip1 in governing CNS myelination. Sip1 inhibits BMP-Smad negative regulatory pathways while activating the expression of crucial myelination-promoting factors. In addition, we identify Smad7, a member of inhibitory Smads (I-Smads) in the Smad pathway, as a key target induced by Sip1. We show that Smad7 is required for oligodendrocyte differentiation and promotes myelination by blocking BMP and Wnt/β-catenin inhibitory pathways. Thus, by antagonizing activated BMP-Smads while inducing the I-Smad gene Smad7, Sip1 exerts dual-mode regulation of Smad signaling to control oligodendrocyte maturation. Our findings reveal a previously unrecognized role for Sip1 in governing myelination and, in addition, its direct modulation of two Smad pathways, pointing to Sip1 as a nodal point that integrates extrinsic signals and intrinsic regulators to control the myelinogenic program in the CNS. To identify the target genes directly regulated by Olig2, we carried out whole-genome ChIP sequencing using purified rat oligodendrocytes.