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...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003955&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841527101334749184 |
|---|---|
| author | Ashish Kumar Maurya Jin Ben Zhonghua Zhao Raymond Teck Ho Lee Weixin Niah Ashley Shu Mei Ng Audrey Iyu Weimiao Yu Stone Elworthy Fredericus J M van Eeden Philip William Ingham |
| author_facet | Ashish Kumar Maurya Jin Ben Zhonghua Zhao Raymond Teck Ho Lee Weixin Niah Ashley Shu Mei Ng Audrey Iyu Weimiao Yu Stone Elworthy Fredericus J M van Eeden Philip William Ingham |
| author_sort | Ashish Kumar Maurya |
| collection | DOAJ |
| 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 | Article |
| id | doaj-art-6a294bb43fd44279a83dd362194a0227 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-6a294bb43fd44279a83dd362194a02272025-01-16T05:31:15ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-01912e100395510.1371/journal.pgen.1003955Positive and negative regulation of Gli activity by Kif7 in the zebrafish embryo.Ashish Kumar MauryaJin BenZhonghua ZhaoRaymond Teck Ho LeeWeixin NiahAshley Shu Mei NgAudrey IyuWeimiao YuStone ElworthyFredericus J M van EedenPhilip William InghamLoss 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003955&type=printable |
| spellingShingle | Ashish Kumar Maurya Jin Ben Zhonghua Zhao Raymond Teck Ho Lee Weixin Niah Ashley Shu Mei Ng Audrey Iyu Weimiao Yu Stone Elworthy Fredericus J M van Eeden Philip William Ingham Positive and negative regulation of Gli activity by Kif7 in the zebrafish embryo. PLoS Genetics |
| 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 |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003955&type=printable |
| work_keys_str_mv | AT ashishkumarmaurya positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT jinben positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT zhonghuazhao positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT raymondteckholee positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT weixinniah positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT ashleyshumeing positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT audreyiyu positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT weimiaoyu positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT stoneelworthy positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT fredericusjmvaneeden positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo AT philipwilliamingham positiveandnegativeregulationofgliactivitybykif7inthezebrafishembryo |