Abstract
A variety of developmental disorders have been associated with ciliary defects, yet the controls that govern cilia disassembly are largely unknown. Here we report a mouse embryonic node gene, which we named Pitchfork (Pifo). Pifo associates with ciliary targeting complexes and accumulates at the basal body during cilia disassembly. Haploinsufficiency causes a unique node cilia duplication phenotype, left-right asymmetry defects, and heart failure. This phenotype is likely relevant in humans, because we identified a heterozygous R80K PIFO mutation in a fetus with situs inversus and cystic liver and kidneys, and in patient with double-outflow right ventricle. We show that PIFO, but not R80K PIFO, is sufficient to activate Aurora A, a protooncogenic kinase that induces cilia retraction, and that Pifo/. PIFO mutation causes cilia retraction, basal body liberation, and overreplication defects. Thus, the observation of a disassembly phenotype in vivo provides an entry point to understand and categorize ciliary disease. Author Audio:
| Original language | English (US) |
|---|---|
| Pages (from-to) | 66-77 |
| Number of pages | 12 |
| Journal | Developmental Cell |
| Volume | 19 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2010 |
Funding
We are extremely grateful to W. Barkey and A. Theis for excellent technical assistance and P. Giallonardo for generation of chimeras. We thank D. Bonnet for DNA samples from DORV patients; L. Jennen for expert help with TEM; E. Nigg for Cep135 and Cep164; K. Kontani and T. Caspary for Arl13b antibodies; C.C. Hui for advice with primary limb bud cultures; B. Bruneau for Bmp2, Bmp4, and Pitx2c and H. Hamada for Cerr2, Nodal, and Lefty1/2 in situ hybridization probes; and P. Liao, E. Drew, M. Goetz, M.J. Plevin, and N. Chadderton for their valuable comments on the manuscript. This work was supported by BMBF Quant Pro (FZK0316865A to M.U.), BMBF Systec-Dynamo (FZK 031155514 to M.U.), and EU 7th FW grant Affinomics (grant agreement no. 241481 to M.U.).This work was also supported by the Helmholtz Society, European Research Council, and German Research Foundation (DFG) with an Emmy-Noether fellowship and a starting grant awarded to H.L.; National Institute of Child Health and Development Grant R01HD04260 (N.K.); National Institute of Diabetes, Digestive, and Kidney Disorders Grants R01DK072301 and R01DK075972 (N.K.); National Research Service Award Fellowship F32 DK079541 (E.E.D.); the Macular Vision Research Foundation (N.K.); EU grant ProteomeBinders (FP6-026008) (M.U.); the German Federal Ministry of Education and Research (BMBF: DYNAMO, FKZ: 0315513A) (M.U.); and the Kerstan Foundation (M.U.).
ASJC Scopus subject areas
- Molecular Biology
- General Biochemistry, Genetics and Molecular Biology
- Developmental Biology
- Cell Biology
