PUBLICATION

Bmp and Nodal Independently Regulate lefty1 Expression to Maintain Unilateral Nodal Activity during Left-Right Axis Specification in Zebrafish

Authors
Smith, K.A., Noël, E., Thurlings, I., Rehmann, H., Chocron, S., and Bakkers, J.
ID
ZDB-PUB-111025-3
Date
2011
Source
PLoS Genetics   7(9): e1002289 (Journal)
Registered Authors
Bakkers, Jeroen, Chocron, Sonja, Noël, Emily, Smith, Kelly
Keywords
Embryos, BMP signaling, Zebrafish, In situ hybridization, Phenotypes, Cilia, Genetic screens, Library screening
MeSH Terms
  • Mutant Proteins/chemistry
  • Mutant Proteins/genetics
  • Embryonic Development/genetics*
  • Activin Receptors, Type I/genetics
  • Activin Receptors, Type I/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Bone Morphogenetic Protein Receptors, Type I/genetics*
  • Bone Morphogenetic Protein Receptors, Type I/metabolism
  • Animals
  • Zebrafish/genetics
  • Zebrafish/growth & development*
  • Body Patterning/genetics
  • Signal Transduction
  • Mutation, Missense
  • Left-Right Determination Factors/genetics*
  • Left-Right Determination Factors/metabolism
  • Nodal Protein/genetics*
  • Nodal Protein/metabolism
  • Bone Morphogenetic Proteins/genetics*
  • Bone Morphogenetic Proteins/metabolism
(all 21)
PubMed
21980297 Full text @ PLoS Genet.
Abstract

In vertebrates, left-right (LR) axis specification is determined by a ciliated structure in the posterior region of the embryo. Fluid flow in this ciliated structure is responsible for the induction of unilateral left-sided Nodal activity in the lateral plate mesoderm, which in turn regulates organ laterality. Bmp signalling activity has been implied in repressing Nodal expression on the right side, however its mechanism of action has been controversial. In a forward genetic screen for mutations that affect LR patterning, we identified the zebrafish linkspoot (lin) mutant, characterized by cardiac laterality and mild dorsoventral patterning defects. Mapping of the lin mutation revealed an inactivating missense mutation in the Bmp receptor 1aa (bmpr1aa) gene. Embryos with a mutation in lin/bmpr1aa and a novel mutation in its paralogue, bmpr1ab, displayed a variety of dorsoventral and LR patterning defects with increasing severity corresponding with a decrease in bmpr1a dosage. In Bmpr1a-deficient embryos we observed bilateral expression of the Nodal-related gene, spaw, coupled with reduced expression of the Nodal-antagonist lefty1 in the midline. Using genetic models to induce or repress Bmp activity in combination with Nodal inhibition or activation, we found that Bmp and Nodal regulate lefty1 expression in the midline independently of each other. Furthermore, we observed that the regulation of lefty1 by Bmp signalling is required for its observed downregulation of Nodal activity in the LPM providing a novel explanation for this phenomenon. From these results we propose a two-step model in which Bmp regulates LR patterning. Prior to the onset of nodal flow and Nodal activation, Bmp is required to induce lefty1 expression in the midline. When nodal flow has been established and Nodal activity is apparent, both Nodal and Bmp independently are required for lefty1 expression to assure unilateral Nodal activation and correct LR patterning.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
fr13TgTransgenic Insertion
    fr14TgTransgenic Insertion
      hu255H
        Point Mutation
        hu4087
          Point Mutation
          sa28
            Point Mutation
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            lft1MO4-lft1MRPHLNO
            1 - 1 of 1
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            Fish
            Antibodies
            No data available
            Orthology
            No data available
            Engineered Foreign Genes
            No data available
            Mapping
            Entity Type Entity Symbol Location
            Featurehu4087Chr: 13 Details
            GENEbmpr1aaChr: 13 Details
            SSLPz6259Chr: 13 Details
            SSLPz17223Chr: 13 Details
            1 - 4 of 4
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