TY - JOUR
T1 - Dual-Mode Modulation of Smad Signaling by Smad-Interacting Protein Sip1 Is Required for Myelination in the Central Nervous System
AU - Weng, Qinjie
AU - Chen, Ying
AU - Wang, Haibo
AU - Xu, Xiaomei
AU - Yang, Bo
AU - He, Qiaojun
AU - Shou, Weinian
AU - Chen, Yan
AU - Higashi, Yujiro
AU - van den Berghe, Veronique
AU - Seuntjens, Eve
AU - Kernie, Steven G.
AU - Bukshpun, Polina
AU - Sherr, Elliott H.
AU - Huylebroeck, Danny
AU - Lu, Richard R.
N1 - Funding Information:
The authors would like to thank Y. Yu, A. Nishiyama, B. Kim, W. Liu, L. Liu, C. Shen, Melinda K. Duncan, and A. Francis and A. Conidi for technical support. We thank C. Stiles, J. Svaren, S. Yoon, E. Olson, J. Johnson, J. Li, E. Hurlock, N. Ma, and O. Barca-Mayo for critical comments and suggestions. This study was funded in part by grants from the National Institutes of Health (R01NS072427) and the National Multiple Sclerosis Society (RG3978) (to Q.R.L.) and the Research Council of Katholieke Universiteit Leuven (OT-09/053 and GOA-11/012), FWO-V (G.0954.11N to D.H. and E.S.), the Queen Elisabeth Medical Foundation (GSKE 1113) and Interuniversity Attraction Poles (IUAP 6/20), and the type 3 large-infrastructure support InfraMouse by the Hercules Foundation (to D.H.).
PY - 2012/2/23
Y1 - 2012/2/23
N2 - 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. Weng et al. find the transcription factor Sip1 governs myelination by modulating Smad signaling and reveal a key Sip1-induced target, Smad7, which promotes oligodendrocyte differentiation by blocking BMP and β-catenin negative regulatory pathways.
AB - 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. Weng et al. find the transcription factor Sip1 governs myelination by modulating Smad signaling and reveal a key Sip1-induced target, Smad7, which promotes oligodendrocyte differentiation by blocking BMP and β-catenin negative regulatory pathways.
UR - http://www.scopus.com/inward/record.url?scp=84863128025&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863128025&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2011.12.021
DO - 10.1016/j.neuron.2011.12.021
M3 - Article
C2 - 22365546
AN - SCOPUS:84863128025
SN - 0896-6273
VL - 73
SP - 713
EP - 728
JO - Neuron
JF - Neuron
IS - 4
ER -