TY - JOUR
T1 - Lefty proteins are long-range inhibitors of Squint-mediated Nodal signaling
AU - Chen, Yu
AU - Schier, Alexander F.
N1 - Funding Information:
We thank members of the Schier and Yelon laboratories for discussions; Rebecca Burdine, Amanda Carmany-Rampey, Nathalia Glickman, Kathy Joubin, Hans Meinhardt, Alvaro Sagasti, Will Talbot, and Debbie Yelon for comments on the manuscript; and S. Zimmerman, T. Bruno, and N. Dillon for fish care. Y.C. is the Rebecca Ridley Kry Fellow of the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation. A.F.S. is a Scholar of the McKnight Endowment Fund for Neuroscience, an Irma T. Hirschl Trust Career Scientist, and an Established Investigator of the American Heart Association and is supported by grants from the National Institutes of Health.
PY - 2002/12/23
Y1 - 2002/12/23
N2 - The regulation of signaling pathways by feedback inhibitors has become an emerging theme in the control of pattern formation during development [1]. Nodal and Lefty proteins belong to divergent subfamilies of the TGF-β family [2-5]. Nodal signals promote mesendoderm induction in vertebrates, and Lefty proteins antagonize it [2-5]. In zebrafish, Squint functions as a long-range Nodal signal during mesoderm induction [6]. We report that the range over which Squint induces mesoderm is reduced by Lefty proteins. In contrast, the activity range of the short-range Nodal signal Cyclops is not regulated by Lefty activity. We present three lines of evidence that Lefty proteins diminish the range of Squint signaling by acting not only as antagonists of Squint autoregulation but also as long-range inhibitors of Squint activity. First, Lefty can block Nodal signaling at a distance. Second, Lefty regulates the range of Squint signaling before regulating squint expression. Third, Lefty restricts the range of Squint activity in squint mutant embryos, in which the endogenous gene is not subject to autoregulation. We also find that Lefty restricts the response to both high and low levels of Nodal signaling. These results indicate that Lefty proteins restrict the activity range of Nodal signals by dampening Nodal signaling in surrounding cells.
AB - The regulation of signaling pathways by feedback inhibitors has become an emerging theme in the control of pattern formation during development [1]. Nodal and Lefty proteins belong to divergent subfamilies of the TGF-β family [2-5]. Nodal signals promote mesendoderm induction in vertebrates, and Lefty proteins antagonize it [2-5]. In zebrafish, Squint functions as a long-range Nodal signal during mesoderm induction [6]. We report that the range over which Squint induces mesoderm is reduced by Lefty proteins. In contrast, the activity range of the short-range Nodal signal Cyclops is not regulated by Lefty activity. We present three lines of evidence that Lefty proteins diminish the range of Squint signaling by acting not only as antagonists of Squint autoregulation but also as long-range inhibitors of Squint activity. First, Lefty can block Nodal signaling at a distance. Second, Lefty regulates the range of Squint signaling before regulating squint expression. Third, Lefty restricts the range of Squint activity in squint mutant embryos, in which the endogenous gene is not subject to autoregulation. We also find that Lefty restricts the response to both high and low levels of Nodal signaling. These results indicate that Lefty proteins restrict the activity range of Nodal signals by dampening Nodal signaling in surrounding cells.
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U2 - 10.1016/S0960-9822(02)01362-3
DO - 10.1016/S0960-9822(02)01362-3
M3 - Article
C2 - 12498687
AN - SCOPUS:0037164725
SN - 0960-9822
VL - 12
SP - 2124
EP - 2128
JO - Current Biology
JF - Current Biology
IS - 24
ER -