title: BMP signaling through ACVRI is required for left-right patterning in the early mouse embryo.
abstract: Vertebrate organisms are characterized by dorsal-ventral and left-right asymmetry. The process that establishes left-right asymmetry during vertebrate development involves bone morphogenetic protein (BMP)-dependent signaling, but the molecular details of this signaling pathway remain poorly defined. This study tests the role of the BMP type I receptor ACVRI in establishing left-right asymmetry in chimeric mouse embryos. Mouse embryonic stem (ES) cells with a homozygous deletion at Acvr1 were used to generate chimeric embryos. Chimeric embryos were rescued from the gastrulation defect of Acvr1 null embryos but exhibited abnormal heart looping and embryonic turning. High mutant contribution chimeras expressed left-side markers such as nodal bilaterally in the lateral plate mesoderm (LPM), indicating that loss of ACVRI signaling leads to left isomerism. Expression of lefty1 was absent in the midline of chimeric embryos, but shh, a midline marker, was expressed normally, suggesting that, despite formation of midline, its barrier function was abolished. High-contribution chimeras also lacked asymmetric expression of nodal in the node. These data suggest that ACVRI signaling negatively regulates left-side determinants such as nodal and positively regulates lefty1. These functions maintain the midline, restrict expression of left-side markers, and are required for left-right pattern formation during embryogenesis in the mouse.
authors.affiliation: Molecular Developmental Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishigami
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Yoshikawa
authors.forename: Trisha
authors.initials: T
authors.lastname: Castranio
authors.forename: Kenji
authors.initials: K
authors.lastname: Okazaki
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics*; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D047108:Embryonic Development; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008845:Microinjections; D008954:Models, Biological; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D017978:Receptors, Growth Factor; D017346:Protein Serine-Threonine Kinases; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D001616:beta-Galactosidase