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  current news   Press   selected story    
     
  6 December 2013  
  Positive and Negative Regulation of Gli activity by Kif7 in the Zebrafish embryo
 
 



Authors
Ashish Kumar Maurya1,3,#, Jin Ben1,#, Zhonghua Zhao1,#, Raymond  Teck Ho Lee1, Weixin Niah1, Ashley Shu Mei Ng1, Audrey Iyu1, Weimiao Yu1, Stone Elworthy2, Fredericus J.M. van Eeden2 and Philip William Ingham1,2,3*

1 - A*STAR Institute of Molecular & Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Republic      of Singapore
2 - MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Western Bank,      Sheffield S10 2TN, United Kingdom
3 - Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore      117543, Republic of Singapore

# the first three authors contributed equally to this study

* Corresponding Author: P. W. Ingham

Published in PLOS Genetics on 5 December 2013.

Abstract
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 also present evidence that it mediates the 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 the levels of SuFu protein are reduced. Notably, zebrafish lacking all Kif7 function are viable, in contrast to the perinatal lethality of mouse kif7 mutants but similar to some Acrocollosal or Joubert syndrome patients who are homozygous for loss of function KIF7 alleles.

Figure legend: Kif7 protein localization is modulated by Hh pathway activity

(A-C) Parasagittal optical sections of the neural tube in 20ss embryos, showing the distribution of the endogenous Kif7 protein. In wild-type (A) and smo (B) embryos, Kif7 accumulates in puncta throughout the cytoplasm as well as in the primary cilium. In ptch1; ptch2 double mutant embryos (C) by contrast, the cytoplasmic puncta are completely absent with Kif7 remaining only at the tips of the cilia. Scale bar: 10mm

(D-I) similar distributions of Kif7 are seen in the otic vesicle (D-F) and the myotome (G-I) of wild-type and mutant embryos. Insets show a magnified view of a part of each image; note that Kif7 accumulates at the tips of some primary cilia in wild-type (D,G), smo mutant (E,H) but at elevated levels in all cilia in ptch1;ptch2 double mutant (F,I) embryos. Scale bars: 10mm; Inset scale bar: 1mm

For more information on Philip INGHAM's laboratory, please click here.