Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.

Embryonic axis formation in vertebrates is initiated by the establishment of the dorsal Nieuwkoop blastula organizer, marked by the nuclear accumulation of maternal β-catenin, a transcriptional effector of canonical Wnt signaling. Known regulators of axis specification include the canonical Wnt path...

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Autores principales:	Shu-Yu Wu, Jimann Shin, Diane S Sepich, Lilianna Solnica-Krezel
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8afb28dbe1b7438ca0bf4755aabbdef0
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spelling	oai:doaj.org-article:8afb28dbe1b7438ca0bf4755aabbdef02021-11-18T05:37:24ZChemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.1544-91731545-788510.1371/journal.pbio.1001403https://doaj.org/article/8afb28dbe1b7438ca0bf4755aabbdef02012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23055828/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Embryonic axis formation in vertebrates is initiated by the establishment of the dorsal Nieuwkoop blastula organizer, marked by the nuclear accumulation of maternal β-catenin, a transcriptional effector of canonical Wnt signaling. Known regulators of axis specification include the canonical Wnt pathway components that positively or negatively affect β-catenin. An involvement of G-protein coupled receptors (GPCRs) was hypothesized from experiments implicating G proteins and intracellular calcium in axis formation, but such GPCRs have not been identified. Mobilization of intracellular Ca(2+) stores generates Ca(2+) transients in the superficial blastomeres of zebrafish blastulae when the nuclear accumulation of maternal β-catenin marks the formation of the Nieuwkoop organizer. Moreover, intracellular Ca(2+) downstream of non-canonical Wnt ligands was proposed to inhibit β-catenin and axis formation, but mechanisms remain unclear. Here we report a novel function of Ccr7 GPCR and its chemokine ligand Ccl19.1, previously implicated in chemotaxis and other responses of dendritic cells in mammals, as negative regulators of β-catenin and axis formation in zebrafish. We show that interference with the maternally and ubiquitously expressed zebrafish Ccr7 or Ccl19.1 expands the blastula organizer and the dorsoanterior tissues at the expense of the ventroposterior ones. Conversely, Ccr7 or Ccl19.1 overexpression limits axis formation. Epistatic analyses demonstrate that Ccr7 acts downstream of Ccl19.1 ligand and upstream of β-catenin transcriptional targets. Moreover, Ccl19/Ccr7 signaling reduces the level and nuclear accumulation of maternal β-catenin and its axis-inducing activity and can also inhibit the Gsk3β -insensitive form of β-catenin. Mutational and pharmacologic experiments reveal that Ccr7 functions during axis formation as a GPCR to inhibit β-catenin, likely by promoting Ca(2+) transients throughout the blastula. Our study delineates a novel negative, Gsk3β-independent control mechanism of β-catenin and implicates Ccr7 as a long-hypothesized GPCR regulating vertebrate axis formation.Shu-Yu WuJimann ShinDiane S SepichLilianna Solnica-KrezelPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 10, p e1001403 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Shu-Yu Wu Jimann Shin Diane S Sepich Lilianna Solnica-Krezel Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.
description	Embryonic axis formation in vertebrates is initiated by the establishment of the dorsal Nieuwkoop blastula organizer, marked by the nuclear accumulation of maternal β-catenin, a transcriptional effector of canonical Wnt signaling. Known regulators of axis specification include the canonical Wnt pathway components that positively or negatively affect β-catenin. An involvement of G-protein coupled receptors (GPCRs) was hypothesized from experiments implicating G proteins and intracellular calcium in axis formation, but such GPCRs have not been identified. Mobilization of intracellular Ca(2+) stores generates Ca(2+) transients in the superficial blastomeres of zebrafish blastulae when the nuclear accumulation of maternal β-catenin marks the formation of the Nieuwkoop organizer. Moreover, intracellular Ca(2+) downstream of non-canonical Wnt ligands was proposed to inhibit β-catenin and axis formation, but mechanisms remain unclear. Here we report a novel function of Ccr7 GPCR and its chemokine ligand Ccl19.1, previously implicated in chemotaxis and other responses of dendritic cells in mammals, as negative regulators of β-catenin and axis formation in zebrafish. We show that interference with the maternally and ubiquitously expressed zebrafish Ccr7 or Ccl19.1 expands the blastula organizer and the dorsoanterior tissues at the expense of the ventroposterior ones. Conversely, Ccr7 or Ccl19.1 overexpression limits axis formation. Epistatic analyses demonstrate that Ccr7 acts downstream of Ccl19.1 ligand and upstream of β-catenin transcriptional targets. Moreover, Ccl19/Ccr7 signaling reduces the level and nuclear accumulation of maternal β-catenin and its axis-inducing activity and can also inhibit the Gsk3β -insensitive form of β-catenin. Mutational and pharmacologic experiments reveal that Ccr7 functions during axis formation as a GPCR to inhibit β-catenin, likely by promoting Ca(2+) transients throughout the blastula. Our study delineates a novel negative, Gsk3β-independent control mechanism of β-catenin and implicates Ccr7 as a long-hypothesized GPCR regulating vertebrate axis formation.
format	article
author	Shu-Yu Wu Jimann Shin Diane S Sepich Lilianna Solnica-Krezel
author_facet	Shu-Yu Wu Jimann Shin Diane S Sepich Lilianna Solnica-Krezel
author_sort	Shu-Yu Wu
title	Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.
title_short	Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.
title_full	Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.
title_fullStr	Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.
title_full_unstemmed	Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.
title_sort	chemokine gpcr signaling inhibits β-catenin during zebrafish axis formation.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/8afb28dbe1b7438ca0bf4755aabbdef0
work_keys_str_mv	AT shuyuwu chemokinegpcrsignalinginhibitsbcateninduringzebrafishaxisformation AT jimannshin chemokinegpcrsignalinginhibitsbcateninduringzebrafishaxisformation AT dianessepich chemokinegpcrsignalinginhibitsbcateninduringzebrafishaxisformation AT liliannasolnicakrezel chemokinegpcrsignalinginhibitsbcateninduringzebrafishaxisformation
_version_	1718424861904207872

Chemokine GPCR signaling inhibits β-catenin during zebrafish axis formation.

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