The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking.
Two intraflagellar transport (IFT) complexes, IFT-A and IFT-B, build and maintain primary cilia and are required for activity of the Sonic hedgehog (Shh) pathway. A weak allele of the IFT-A gene, Ift144, caused subtle defects in cilia structure and ectopic activation of the Shh pathway. In contrast, strong loss of IFT-A, caused by either absence of Ift144 or mutations in two IFT-A genes, blocked normal ciliogenesis and decreased Shh signaling. In strong IFT-A mutants, the Shh pathway proteins Gli2, Sufu, and Kif7 localized correctly to cilia tips, suggesting that these pathway components were trafficked by IFT-B. In contrast, the membrane proteins Arl13b, ACIII, and Smo failed to localize to primary cilia in the absence of IFT-A. We propose that the increased Shh activity seen in partial loss-of-function IFT-A mutants may be a result of decreased ciliary ACIII and that the loss of Shh activity in the absence of IFT-A is a result of severe disruptions of cilia structure and membrane protein trafficking.
Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
Karel F
KF
Liem
Alyson
A
Ashe
Mu
M
He
Peter
P
Satir
Jennifer
J
Moran
David
D
Beier
Carol
C
Wicking
Kathryn V
KV
Anderson
D000818:Animals; D002923:Cilia / Q000378:metabolism / Q000648:ultrastructure*; D003598:Cytoskeletal Proteins; D005407:Flagella / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000075746:Zinc Finger Protein Gli2
D003598:Cytoskeletal Proteins; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D011506:Proteins; D012097:Repressor Proteins; C490763:Sufu protein, mouse; C486870:Wdr19 protein, mouse; D000075746:Zinc Finger Protein Gli2; C543639:Kif7 protein, mouse; D016547:Kinesins