Regulation of gut and heart left-right asymmetry by context-dependent interactions between xenopus lefty and BMP4 signaling.
The Lefty subfamily of TGFbeta signaling molecules has been implicated in early development in mouse, zebrafish, and chick. Here, we show that Xenopus lefty (Xlefty) is expressed both bilaterally in symmetric midline domains and unilaterally in left lateral plate mesoderm and anterior dorsal endoderm. To examine the roles of Xlefty in left-right development, we created a system for scoring gut asymmetry and examined the effects of unilateral Xlefty misexpression on gut development, heart development, and Xnr-1 and XPitx2 expression. In contrast to the unilateral effects of Vg1, Activin, Nodal, or BMPs, targeted expression of Xlefty in either the left or the right side of Xenopus embryos randomized the direction of heart looping, gut coiling, and left-right positioning of the gut and downregulated the asymmetric expression of Xnr-1 and XPitx2. It is currently thought that Lefty proteins act as feedback inhibitors of Nodal signaling. However, this would not explain the effects of right-sided Xlefty misexpression. Here, we show that Xlefty interacts with the signaling pathways of other members of the TGFbeta family during left-right development. Results from coexpression of Xlefty and Vg1 indicate that Xlefty can nullify the effects of Vg1 ectopic expression and that Xlefty is downstream of left-sided Vg1 signaling. Results from coexpression of Xlefty and XBMP4 indicate that XLefty and XBMP4 interact both synergistically and antagonistically in a context-dependent manner. We propose a model in which interactions of Xlefty with multiple members of the TGFbeta family enhance the differences between the right-sided BMP/ALK2/Smad pathway and the left-sided Vg1/anti-BMP/Nodal pathway, leading to left-right morphogenesis of the gut and heart.
Branford
W W
WW
Huntsman Cancer Institute, Center for Children, Department of Oncological Sciences and Department of Pediatrics, University of Utah, Salt Lake City, Utah, 84112-5550, USA.
Essner
J J
JJ
Yost
H J
HJ
D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004064:Digestive System / Q000196:embryology*; D004627:Embryonic Induction; D006023:Glycoproteins / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D018398:Homeodomain Proteins / Q000378:metabolism; D053703:Interleukin-11 Receptor alpha Subunit; D055458:Left-Right Determination Factors; D008648:Mesoderm; D008954:Models, Biological; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D018123:Receptors, Interleukin / Q000378:metabolism; D053702:Receptors, Interleukin-11; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D000097577:Homeobox Protein PITX2
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D006023:Glycoproteins; D018398:Homeodomain Proteins; D053703:Interleukin-11 Receptor alpha Subunit; D055458:Left-Right Determination Factors; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D000097577:Homeobox Protein PITX2; C525810:Bmp4 protein, mouse; C513103:GDF1 protein, Xenopus; C508429:Il11ra1 protein, mouse; C525812:bmp4 protein, Xenopus; C525813:bmp4 protein, zebrafish; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3