Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry.
The embryonic midline in vertebrates has been implicated in left-right development, but the mechanisms by which it regulates left-right asymmetric gene expression and organ morphogenesis are unknown. Zebrafish embryos have three domains of left-right asymmetric gene expression that are useful predictors of organ situs. cyclops (nodal), lefty1 and pitx2 are expressed in the left diencephalon; cyclops, lefty2 and pitx2 are expressed in the left heart field; and cyclops and pitx2 are expressed in the left gut primordium. Distinct alterations of these expression patterns in zebrafish midline mutants identify four phenotypic classes that have different degrees of discordance among the brain, heart and gut. These classes help identify two midline domains and several genetic pathways that regulate left-right development. A cyclops-dependent midline domain, associated with the prechordal plate, regulates brain asymmetry but is dispensable for normal heart and gut left-right development. A second midline domain, associated with the anterior notochord, is dependent on no tail, floating head and momo function and is essential for restricting asymmetric gene expression to the left side. Mutants in spadetail or chordino give discordant gene expression among the brain, heart and gut. one-eyed pinhead and schmalspur are necessary for asymmetric gene expression and may mediate signaling from midline domains to lateral tissues. The different phenotypic classes help clarify the apparent disparity of mechanisms proposed to explain left-right development in different vertebrates.
Bisgrove
B W
BW
Huntsman Cancer Institute, Center for Children, Departments of Oncological Sciences and of Pediatrics, University of Utah, Salt Lake City UT 84112, USA.
Essner
J J
JJ
Yost
H J
HJ
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D001921:Brain / Q000196:embryology*; D004027:Diencephalon / Q000196:embryology; D004064:Digestive System / Q000196:embryology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D055458:Left-Right Determination Factors; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D029867:Xenopus Proteins; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins; D000097577:Homeobox Protein PITX2
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D055458:Left-Right Determination Factors; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D000097577:Homeobox Protein PITX2; C525810:Bmp4 protein, mouse; C526161:LEFTY1 protein, human; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; C525812:bmp4 protein, Xenopus; C525813:bmp4 protein, zebrafish; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3; C512832:ndr2 protein, zebrafish; C512833:nodal1 protein, Xenopus