Setdb2 restricts dorsal organizer territory and regulates left-right asymmetry through suppressing fgf8 activity.
Dorsal organizer formation is one of the most critical steps in early embryonic development. Several genes and signaling pathways that positively regulate the dorsal organizer development have been identified; however, little is known about the factor(s) that negatively regulates the organizer formation. Here, we show that Setdb2, a SET domain-containing protein possessing potential histone H3K9 methyltransferase activity, restricts dorsal organizer development and regulates left-right asymmetry by suppressing fibroblast growth factor 8 (fgf8) expression. Knockdown of Setdb2 results in a massive expansion of dorsal organizer markers floating head (flh), goosecoid (gsc), and chordin (chd), as well as a significant increase of fgf8, but not fgf4 mRNAs. Consequently, disrupted midline patterning and resultant randomization of left-right asymmetry are observed in Setdb2-deficient embryos. These characteristic changes induced by Setdb2 deficiency can be nearly corrected by either overexpression of a dominant-negative fgf receptor or knockdown of fgf8, suggesting an essential role for Setdb2-Fgf8 signaling in restricting dorsal organizer territory and regulating left-right asymmetry. These results provide unique evidence that a SET domain-containing protein potentially involved in the epigenetic control negatively regulates dorsal organizer formation during early embryonic development.
Xu
Peng-Fei
PF
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Zhu
Kang-Yong
KY
Jin
Yi
Y
Chen
Yi
Y
Sun
Xiao-Jian
XJ
Deng
Min
M
Chen
Sai-Juan
SJ
Chen
Zhu
Z
Liu
Ting Xi
TX
D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism*; D051524:Fibroblast Growth Factor 8 / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000235:genetics; D051956:Goosecoid Protein / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics*
D006023:Glycoproteins; D051956:Goosecoid Protein; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D029961:Zebrafish Proteins; C497995:gsc protein, zebrafish; C096660:noto protein, zebrafish; D051524:Fibroblast Growth Factor 8; C054234:chordin; D011495:Histone-Lysine N-Methyltransferase; C549064:Setdb2 protein, zebrafish