title: Smad6 promotes neuronal differentiation in the intermediate zone of the dorsal neural tube by inhibition of the Wnt/beta-catenin pathway.
abstract: Proliferation of the neural/neuronal progenitor cells (NPCs) at the ventricular zone of the dorsal spinal cord requires the stimuli of Wnt and bone morphogenic protein (BMP). However, how these two signaling pathways are regulated to initiate differentiation in the NPCs as they enter the intermediate zone is not known. Here, we show that Smad6, a negative regulator of BMP signaling, is expressed in the intermediate zone of the chick dorsal spinal cord. Knockdown experiments show that Smad6 is required for promoting NPCs to exit the cell cycle and differentiate into neurons. Although we find that Smad6 inhibits BMP signaling, as expected, we also find that Smad6 unexpectedly inhibits the Wnt/β-catenin pathway. The inhibition of the Wnt/β-catenin pathway by Smad6 is independent of its effect on the BMP pathway. Rather, Smad6 through its N-terminal domain and link region enhances the interaction of C-terminal binding protein with the β-catenin/T cell factor (TCF) complex and the TCF-binding element to inhibit β-catenin-mediated transcriptional activation. Our study provides evidence that transition of NPCs from a proliferative state to a differentiating state is controlled by the dual inhibitory role of Smad6 to both BMP and Wnt signaling at the level of transcription.
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Zhihui
authors: Z
authors: Xie
authors: Yongfeng
authors: Y
authors: Chen
authors: Zhenfei
authors: Z
authors: Li
authors: Ge
authors: G
authors: Bai
authors: Yue
authors: Y
authors: Zhu
authors: Rui
authors: R
authors: Yan
authors: Fangzhi
authors: F
authors: Tan
authors: Ye-Guang
authors: YG
authors: Chen
authors: Francois
authors: F
authors: Guillemot
authors: Lin
authors: L
authors: Li
authors: Naihe
authors: N
authors: Jing
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000502:physiology*; D002642:Chick Embryo; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D018274:Electroporation; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008156:Luciferases; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D017931:DNA Primers; D051905:Smad6 Protein; D051153:Wnt Proteins; D051176:beta Catenin; D008156:Luciferases; D001973:Bromodeoxyuridine