Neuron
Volume 73, Issue 4, 23 February 2012, Pages 713-728
Journal home page for Neuron

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

https://doi.org/10.1016/j.neuron.2011.12.021Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Zinc finger homeobox transcription factor Sip1/Zfhx1b is required for CNS myelination ► Sip1 promotes CNS myelination by modulating BMP-Smad signaling activity ► Identification of a new oligodendrocyte-enriched gene Smad7 as a key Sip1 target ► Smad7 is both sufficient and critical for oligodendrocyte differentiation

Cited by (0)

10

These authors contributed equally to this work