Cargando…

Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo

Loss of function mutations of Kif7, the vertebrate orthologue of the Drosophila Hh pathway component Costal2, cause defects in the limbs and neural tubes of mice, attributable to ectopic expression of Hh target genes. While this implies a functional conservation of Cos2 and Kif7 between flies and ve...

Descripción completa

Detalles Bibliográficos
Autores principales: Maurya, Ashish Kumar, Ben, Jin, Zhao, Zhonghua, Lee, Raymond Teck Ho, Niah, Weixin, Ng, Ashley Shu Mei, Iyu, Audrey, Yu, Weimiao, Elworthy, Stone, van Eeden, Fredericus J. M., Ingham, Philip William
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854788/
https://www.ncbi.nlm.nih.gov/pubmed/24339784
http://dx.doi.org/10.1371/journal.pgen.1003955
_version_ 1782294861189218304
author Maurya, Ashish Kumar
Ben, Jin
Zhao, Zhonghua
Lee, Raymond Teck Ho
Niah, Weixin
Ng, Ashley Shu Mei
Iyu, Audrey
Yu, Weimiao
Elworthy, Stone
van Eeden, Fredericus J. M.
Ingham, Philip William
author_facet Maurya, Ashish Kumar
Ben, Jin
Zhao, Zhonghua
Lee, Raymond Teck Ho
Niah, Weixin
Ng, Ashley Shu Mei
Iyu, Audrey
Yu, Weimiao
Elworthy, Stone
van Eeden, Fredericus J. M.
Ingham, Philip William
author_sort Maurya, Ashish Kumar
collection PubMed
description Loss of function mutations of Kif7, the vertebrate orthologue of the Drosophila Hh pathway component Costal2, cause defects in the limbs and neural tubes of mice, attributable to ectopic expression of Hh target genes. While this implies a functional conservation of Cos2 and Kif7 between flies and vertebrates, the association of Kif7 with the primary cilium, an organelle absent from most Drosophila cells, suggests their mechanisms of action may have diverged. Here, using mutant alleles induced by Zinc Finger Nuclease-mediated targeted mutagenesis, we show that in zebrafish, Kif7 acts principally to suppress the activity of the Gli1 transcription factor. Notably, we find that endogenous Kif7 protein accumulates not only in the primary cilium, as previously observed in mammalian cells, but also in cytoplasmic puncta that disperse in response to Hh pathway activation. Moreover, we show that Drosophila Costal2 can substitute for Kif7, suggesting a conserved mode of action of the two proteins. We show that Kif7 interacts with both Gli1 and Gli2a and suggest that it functions to sequester Gli proteins in the cytoplasm, in a manner analogous to the regulation of Ci by Cos2 in Drosophila. We also show that zebrafish Kif7 potentiates Gli2a activity by promoting its dissociation from the Suppressor of Fused (Sufu) protein and present evidence that it mediates a Smo dependent modification of the full length form of Gli2a. Surprisingly, the function of Kif7 in the zebrafish embryo appears restricted principally to mesodermal derivatives, its inactivation having little effect on neural tube patterning, even when Sufu protein levels are depleted. Remarkably, zebrafish lacking all Kif7 function are viable, in contrast to the peri-natal lethality of mouse kif7 mutants but similar to some Acrocallosal or Joubert syndrome patients who are homozygous for loss of function KIF7 alleles.
format Online
Article
Text
id pubmed-3854788
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-38547882013-12-11 Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo Maurya, Ashish Kumar Ben, Jin Zhao, Zhonghua Lee, Raymond Teck Ho Niah, Weixin Ng, Ashley Shu Mei Iyu, Audrey Yu, Weimiao Elworthy, Stone van Eeden, Fredericus J. M. Ingham, Philip William PLoS Genet Research Article Loss of function mutations of Kif7, the vertebrate orthologue of the Drosophila Hh pathway component Costal2, cause defects in the limbs and neural tubes of mice, attributable to ectopic expression of Hh target genes. While this implies a functional conservation of Cos2 and Kif7 between flies and vertebrates, the association of Kif7 with the primary cilium, an organelle absent from most Drosophila cells, suggests their mechanisms of action may have diverged. Here, using mutant alleles induced by Zinc Finger Nuclease-mediated targeted mutagenesis, we show that in zebrafish, Kif7 acts principally to suppress the activity of the Gli1 transcription factor. Notably, we find that endogenous Kif7 protein accumulates not only in the primary cilium, as previously observed in mammalian cells, but also in cytoplasmic puncta that disperse in response to Hh pathway activation. Moreover, we show that Drosophila Costal2 can substitute for Kif7, suggesting a conserved mode of action of the two proteins. We show that Kif7 interacts with both Gli1 and Gli2a and suggest that it functions to sequester Gli proteins in the cytoplasm, in a manner analogous to the regulation of Ci by Cos2 in Drosophila. We also show that zebrafish Kif7 potentiates Gli2a activity by promoting its dissociation from the Suppressor of Fused (Sufu) protein and present evidence that it mediates a Smo dependent modification of the full length form of Gli2a. Surprisingly, the function of Kif7 in the zebrafish embryo appears restricted principally to mesodermal derivatives, its inactivation having little effect on neural tube patterning, even when Sufu protein levels are depleted. Remarkably, zebrafish lacking all Kif7 function are viable, in contrast to the peri-natal lethality of mouse kif7 mutants but similar to some Acrocallosal or Joubert syndrome patients who are homozygous for loss of function KIF7 alleles. Public Library of Science 2013-12-05 /pmc/articles/PMC3854788/ /pubmed/24339784 http://dx.doi.org/10.1371/journal.pgen.1003955 Text en © 2013 Maurya 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
Maurya, Ashish Kumar
Ben, Jin
Zhao, Zhonghua
Lee, Raymond Teck Ho
Niah, Weixin
Ng, Ashley Shu Mei
Iyu, Audrey
Yu, Weimiao
Elworthy, Stone
van Eeden, Fredericus J. M.
Ingham, Philip William
Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo
title Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo
title_full Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo
title_fullStr Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo
title_full_unstemmed Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo
title_short Positive and Negative Regulation of Gli Activity by Kif7 in the Zebrafish Embryo
title_sort positive and negative regulation of gli activity by kif7 in the zebrafish embryo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854788/
https://www.ncbi.nlm.nih.gov/pubmed/24339784
http://dx.doi.org/10.1371/journal.pgen.1003955
work_keys_str_mv AT mauryaashishkumar positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT benjin positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT zhaozhonghua positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT leeraymondteckho positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT niahweixin positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT ngashleyshumei positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT iyuaudrey positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT yuweimiao positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT elworthystone positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT vaneedenfredericusjm positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo
AT inghamphilipwilliam positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo