tbx6 regulates leftright patterning in mouse embryos through effects on nodal cilia and perinodal signalingtbx6调节leftright模式在小鼠胚胎通过对节点纤毛和perinodal信号的影响.pdf

Tbx6 Regulates Left/Right Patterning in Mouse Embryos through Effects on Nodal Cilia and Perinodal Signaling 2 1 1 Anna-Katerina Hadjantonakis , Elinor Pisano , Virginia E. Papaioannou * 1 Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America, 2 Developmental Biology Program, Sloan-Kettering Institute, New York, New York, United States of America Abstract 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 genetic