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Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling

BACKGROUND: The determination of left/right body axis during early embryogenesis sets up a developmental cascade that coordinates the development of the viscera and is essential to the correct placement and alignment of organ systems and vasculature. Defective left-right patterning can lead to conge...

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Autores principales: Hadjantonakis, Anna-Katerina, Pisano, Elinor, Papaioannou, Virginia E.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427182/
https://www.ncbi.nlm.nih.gov/pubmed/18575602
http://dx.doi.org/10.1371/journal.pone.0002511
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author Hadjantonakis, Anna-Katerina
Pisano, Elinor
Papaioannou, Virginia E.
author_facet Hadjantonakis, Anna-Katerina
Pisano, Elinor
Papaioannou, Virginia E.
author_sort Hadjantonakis, Anna-Katerina
collection PubMed
description BACKGROUND: The determination of left/right body axis during early embryogenesis sets up a developmental cascade that coordinates the development of the viscera and is essential to the correct placement and alignment of organ systems and vasculature. Defective left-right patterning can lead to congenital cardiac malformations, vascular anomalies and other serious health problems. Here we describe a novel role for the T-box transcription factor gene Tbx6 in left/right body axis determination in the mouse. RESULTS: Embryos lacking Tbx6 show randomized embryo turning and heart looping. Our results point to multiple mechanisms for this effect. First, Dll1, a direct target of Tbx6, is down regulated around the node in Tbx6 mutants and there is a subsequent decrease in nodal signaling, which is required for laterality determination. Secondly, in spite of a lack of expression of Tbx6 in the node, we document a profound effect of the Tbx6 mutation on the morphology and motility of nodal cilia. This results in the loss of asymmetric calcium signaling at the periphery of the node, suggesting that unidirectional nodal flow is disrupted. To carry out these studies, we devised a novel method for direct labeling and live imaging cilia in vivo using a genetically-encoded fluorescent protein fusion that labels tubulin, combined with laser point scanning confocal microscopy for direct visualization of cilia movement. CONCLUSIONS: We conclude that the transcription factor gene Tbx6 is essential for correct left/right axis determination in the mouse and acts through effects on notch signaling around the node as well as through an effect on the morphology and motility of the nodal cilia.
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spelling pubmed-24271822008-06-25 Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling Hadjantonakis, Anna-Katerina Pisano, Elinor Papaioannou, Virginia E. PLoS One Research Article BACKGROUND: The determination of left/right body axis during early embryogenesis sets up a developmental cascade that coordinates the development of the viscera and is essential to the correct placement and alignment of organ systems and vasculature. Defective left-right patterning can lead to congenital cardiac malformations, vascular anomalies and other serious health problems. Here we describe a novel role for the T-box transcription factor gene Tbx6 in left/right body axis determination in the mouse. RESULTS: Embryos lacking Tbx6 show randomized embryo turning and heart looping. Our results point to multiple mechanisms for this effect. First, Dll1, a direct target of Tbx6, is down regulated around the node in Tbx6 mutants and there is a subsequent decrease in nodal signaling, which is required for laterality determination. Secondly, in spite of a lack of expression of Tbx6 in the node, we document a profound effect of the Tbx6 mutation on the morphology and motility of nodal cilia. This results in the loss of asymmetric calcium signaling at the periphery of the node, suggesting that unidirectional nodal flow is disrupted. To carry out these studies, we devised a novel method for direct labeling and live imaging cilia in vivo using a genetically-encoded fluorescent protein fusion that labels tubulin, combined with laser point scanning confocal microscopy for direct visualization of cilia movement. CONCLUSIONS: We conclude that the transcription factor gene Tbx6 is essential for correct left/right axis determination in the mouse and acts through effects on notch signaling around the node as well as through an effect on the morphology and motility of the nodal cilia. Public Library of Science 2008-06-25 /pmc/articles/PMC2427182/ /pubmed/18575602 http://dx.doi.org/10.1371/journal.pone.0002511 Text en Hadjantonakis et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hadjantonakis, Anna-Katerina
Pisano, Elinor
Papaioannou, Virginia E.
Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling
title Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling
title_full Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling
title_fullStr Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling
title_full_unstemmed Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling
title_short Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling
title_sort tbx6 regulates left/right patterning in mouse embryos through effects on nodal cilia and perinodal signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427182/
https://www.ncbi.nlm.nih.gov/pubmed/18575602
http://dx.doi.org/10.1371/journal.pone.0002511
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