Inhibition of excess nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1.
The formation and patterning of mesoderm during mammalian gastrulation require the activity of Nodal, a secreted mesoderm-inducing factor of the transforming growth factor-beta (TGF-beta) family. Here we show that the transcriptional corepressor DRAP1 has a very specific role in regulation of Nodal activity during mouse embryogenesis. We find that loss of Drap1 leads to severe gastrulation defects that are consistent with increased expression of Nodal and can be partially suppressed by Nodal heterozygosity. Biochemical studies indicate that DRAP1 interacts with and inhibits DNA binding by the winged-helix transcription factor FoxH1 (FAST), a critical component of a positive feedback loop for Nodal activity. We propose that DRAP1 limits the spread of a morphogenetic signal by down-modulating the response to the Nodal autoregulatory loop.
Iratni
Rabah
R
Howard Hughes Medical Institute and Department of Biochemistry, Division of Nucleic Acids Enzymology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Yan
Yu-Ting
YT
Chen
Canhe
C
Ding
Jixiang
J
Zhang
Yi
Y
Price
Sandy M
SM
Reinberg
Danny
D
Shen
Michael M
MM
D000483:Alleles; D000818:Animals; D002460:Cell Line; D003433:Crosses, Genetic; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005314:Embryonic and Fetal Development; D005260:Female; D051858:Forkhead Transcription Factors; D005775:Gastrula / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006579:Heterozygote; D017403:In Situ Hybridization; D055458:Left-Right Determination Factors; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D009024:Morphogenesis; D009154:Mutation; D055457:Nodal Protein; D010641:Phenotype; D011485:Protein Binding; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C484382:Drap1 protein, mouse; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D055458:Left-Right Determination Factors; D055457:Nodal Protein; C526008:Nodal protein, mouse; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004247:DNA