Human Molecular Genetics Advance Access published online on October 29, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn356
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Convergent Extension Movements and Ciliary Function are Mediated by ofd1, A Zebrafish Orthologue of the Human Oral-Facial-Digital Type 1 Syndrome Gene
1 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK 2 Nephro-Urology Unit, UCL Institute of Child Health, London WC1 N 1EH, UK 3 Department of Cell and Developmental Biology, UCL, London WC1E 6BT, UK
* Correspondence may be addressed to: Derek L. Stemple, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. Tel: +44 (0)1223 496857, FAX: +44 (0)1223 494919, ds4{at}sanger.ac.uk
Received July 22, 2008; Revised October 26, 2008; Accepted October 26, 2008
In humans, OFD1 is mutated in oral-facial-digital type I syndrome leading to prenatal death in hemizygous males and dysmorphic faces and brain malformations, with polycystic kidneys presenting later in life in heterozygous females. To elucidate the function of Ofd1, we have studied its function during zebrafish embryonic development. In wild-type embryos, ofd1 mRNA is widely expressed and Ofd1-GFP fusion protein localizes to the centrosome/basal body. Disrupting Ofd1 using antisense morpholinos (MOs) led to bent body axes, hydrocephalus and oedema. Laterality was randomised in the brain, heart and viscera, likely a consequence of shorter cilia with disrupted axonemes and perturbed intravesicular fluid flow in Kupffer's vesicle. Embryos injected with ofd1 MOs also displayed convergent extension (CE) defects, which were enhanced by loss of Slb/Wnt11 or Tri/Vangl2, two proteins functioning in a non-canonical Wnt/Planar Cell Polarity (PCP) pathway. Pronephric glomerular midline fusion was compromised in vangl2 and ofd1 loss of function embryos and we suggest this anomaly may be a novel CE defect. Thus, Ofd1 is required for ciliary motility and function in zebrafish, supporting data showing that Ofd1 is essential for primary cilia function in mice. In addition, our data show that Ofd1 is important for CE during gastrulation, consistent with data linking primary cilia and non-canonical Wnt/PCP signalling.
# The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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