title: The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis.
abstract: Dorsoventral patterning of the embryonic axis relies upon the mutual antagonism of competing signaling pathways to establish a balance between ventralizing BMP signaling and dorsal cell fate specification mediated by the organizer. In zebrafish, the initial embryo-wide domain of BMP signaling is refined into a morphogenetic gradient following activation dorsally of a maternal Wnt pathway. The accumulation of β-catenin in nuclei on the dorsal side of the embryo then leads to repression of BMP signaling dorsally and the induction of dorsal cell fates mediated by Nodal and FGF signaling. A separate Wnt pathway operates zygotically via Wnt8a to limit dorsal cell fate specification and maintain the expression of ventralizing genes in ventrolateral domains. We have isolated a recessive dorsalizing maternal-effect mutation disrupting the gene encoding Integrator Complex Subunit 6 (Ints6). Due to widespread de-repression of dorsal organizer genes, embryos from mutant mothers fail to maintain expression of BMP ligands, fail to fully express vox and ved, two mediators of Wnt8a, display delayed cell movements during gastrulation, and severe dorsalization. Consistent with radial dorsalization, affected embryos display multiple independent axial domains along with ectopic dorsal forerunner cells. Limiting Nodal signaling or restoring BMP signaling restores wild-type patterning to affected embryos. Our results are consistent with a novel role for Ints6 in restricting the vertebrate organizer to a dorsal domain in embryonic patterning.
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Department of Cell and Developmental Biology, Philadelphia, Pennsylvania, United States of America.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Kapp
authors.forename: Elliott W
authors.initials: EW
authors.lastname: Abrams
authors.forename: Florence L
authors.initials: FL
authors.lastname: Marlow
authors.forename: Mary C
authors.initials: MC
authors.lastname: Mullins
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000595174:Ints6 protein, zebrafish; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C094521:wnt8a protein, zebrafish; D053487:DEAD-box RNA Helicases