XSip1 neuralizing activity involves the co-repressor CtBP and occurs through BMP dependent and independent mechanisms.
The DNA-binding transcription factor Smad-interacting protein-1 (Sip1) (also named Zfhx1b/ZEB2) plays essential roles in vertebrate embryogenesis. In Xenopus, XSip1 is essential at the gastrula stage for neural tissue formation, but the precise molecular mechanisms that underlie this process have not been fully identified yet. Here we show that XSip1 functions as a transcriptional repressor during neural induction. We observed that constitutive activation of BMP signaling prevents neural induction by XSip1 but not the inhibition of several epidermal genes. We provide evidence that XSip1 binds directly to the BMP4 proximal promoter and modulates its activity. Finally, by deletion and mutational analysis, we show that XSip1 possesses multiple repression domains and that CtBPs contribute to its repression activity. Consistent with this, interference with XCtBP function reduced XSip1 neuralizing activity. These results suggest that Sip1 acts in neural tissue formation through direct repression of BMP4 but that BMP-independent mechanisms are involved as well. Our data also provide the first demonstration of the importance of CtBP binding in Sip1 transcriptional activity in vivo.
van Grunsven
Leo A
LA
Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology, Celgen, Division of Molecular and Developmental Genetics, K.U. Leuven VIB, Leuven, Belgium.
Taelman
Vincent
V
Michiels
Christine
C
Verstappen
Griet
G
Souopgui
Jacob
J
Nichane
Massimo
M
Moens
Emmanuelle
E
Opdecamp
Karin
K
Vanhomwegen
Jessica
J
Kricha
Sadia
S
Huylebroeck
Danny
D
Bellefroid
Eric J
EJ
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004475:Ectoderm / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus / Q000033:anatomy & histology / Q000196:embryology* / Q000235:genetics; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D029867:Xenopus Proteins; C492364:ZEB2 protein, Xenopus; C525812:bmp4 protein, Xenopus; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein