Pitchfork regulates primary cilia disassembly and left-right asymmetry.
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:
Kinzel
Doris
D
Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Boldt
Karsten
K
Davis
Erica E
EE
Burtscher
Ingo
I
Trümbach
Dietrich
D
Diplas
Bill
B
Attié-Bitach
Tania
T
Wurst
Wolfgang
W
Katsanis
Nicholas
N
Ueffing
Marius
M
Lickert
Heiko
H
D000595:Amino Acid Sequence; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D019521:Body Patterning / Q000235:genetics* / Q000502:physiology*; D018385:Centrosome / Q000648:ultrastructure; D002923:Cilia / Q000235:genetics* / Q000502:physiology* / Q000648:ultrastructure; D004310:Double Outlet Right Ventricle / Q000235:genetics; D005260:Female; D005801:Genes, Homeobox; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000196:embryology / Q000235:genetics; D008099:Liver / Q000002:abnormalities; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D012857:Situs Inversus / Q000196:embryology / Q000235:genetics
D018398:Homeodomain Proteins; C551745:pitchfork protein, mouse; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases