Our unprecedented observations of Sip1-Smad7 regulatory cascade for OPC differentiation by antagonizing BMP signaling fit in a general picture where the BMP pathway is regulated by various mechanisms, including synexpression and negative feedback mechanisms. In our case, forced expression of Smad7 not only inhibits BMS-907351 mouse BMP signaling in OPCs, but also leads to downregulation of β-catenin levels through a mechanism involving Smad7 and its cognate E3 ubiquitin ligase Smurf1, suggesting that Smad7 can block both BMP and β-catenin negative regulatory pathways for oligodendrocyte differentiation. Importantly, we show that Smad7 overexpression

is able to promote differentiation of OPCs even in the absence of Sip1 and induce oligodendrocyte formation from their precursors in ovo ( Figure S5), suggesting that Smad7 acts downstream of Sip1 as a potent positive regulator for oligodendrocyte differentiation. These findings reveal a previously unrecognized pivotal role of Smad7 in promoting myelination at least in part through antagonizing BMP and β-catenin negative regulatory pathways. Human mutations in SIP1/ZFHX1B cause Mowat-Wilson syndrome (MWS), which is characterized by the combination of defects with variable penetrance, learn more including

severe mental retardation, white matter defects such as corpus callosum agenesis, Hirschsprung disease, and variable congenital malformations such as heart and craniofacial defects ( Dastot-Le Moal et al., 2007, Garavelli and Mainardi, 2007 and Zweier et al., 2005). This old single-gene disorder also leads to delayed motor development, seizures, and epilepsy in many MWS patients. Although Sip1 is critical for neurogenesis in the embryonic cortex ( Seuntjens et al., 2009), the critical role of Sip1 in CNS myelination discovered here through oligodendrocyte lineage-specific

mutagenesis suggests that mutations in SIP1/ZFHX1B may contribute to delayed myelination and white matter defects seen in patients with MWS ( Figure S6) ( Schell-Apacik et al., 2008 and Sztriha et al., 2003). In addition, by using a lysolecithin-induced demyelination/remyelination animal model, we found that Sip1 was substantially upregulated in oligodendrocyte lineage cells in the lesion during remyelination ( Figure S7), pointing to a potential important role of Sip1 in the remyelination process. As an integral component of the Smad regulatory circuitry, Sip1 may represent a novel molecular node of the regulatory network that integrates and balances negative signaling pathways and transcriptional signals to govern CNS myelinogenesis, and perhaps other neurological aspects. Modulation of the Smad signaling pathway may provide a future effective means to promote brain repair in patients with devastating demyelinating diseases and other neurological disorders of the CNS.