Pitchfork regulates primary cilia disassembly and left-right asymmetry

Dev Cell. 2010 Jul 20;19(1):66-77. doi: 10.1016/j.devcel.2010.06.005.

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:

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Body Patterning / genetics*
  • Body Patterning / physiology*
  • Centrosome / ultrastructure
  • Cilia / genetics*
  • Cilia / physiology*
  • Cilia / ultrastructure
  • Double Outlet Right Ventricle / genetics
  • Female
  • Genes, Homeobox
  • Heterozygote
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / physiology*
  • Humans
  • Kidney Diseases, Cystic / embryology
  • Kidney Diseases, Cystic / genetics
  • Liver / abnormalities
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Microscopy, Electron, Scanning
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Pregnancy
  • Protein-Serine-Threonine Kinases / physiology
  • Sequence Homology, Amino Acid
  • Situs Inversus / embryology
  • Situs Inversus / genetics

Substances

  • Homeodomain Proteins
  • pitchfork protein, mouse
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases