Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation.
The cilium serves as a cellular antenna by coordinating upstream environmental cues with numerous downstream signaling processes that are indispensable for the function of the cell. This role is supported by the revelation that defects of the cilium underlie an emerging class of human disorders, termed "ciliopathies." Although mounting interest in the cilium has demonstrated the essential role that the organelle plays in vertebrate development, homeostasis, and disease pathogenesis, the mechanisms regulating cilia morphology and function remain unclear. Here, we show that the target-of-rapamycin (TOR) growth pathway modulates cilia size and function during zebrafish development. Knockdown of tuberous sclerosis complex 1a (tsc1a), which encodes an upstream inhibitor of TOR complex 1 (Torc1), increases cilia length. In contrast, treatment of embryos with rapamycin, an inhibitor of Torc1, shortens cilia length. Overexpression of ribosomal protein S6 kinase 1 (S6k1), which encodes a downstream substrate of Torc1, lengthens cilia. Furthermore, we provide evidence that TOR-mediated cilia assembly is evolutionarily conserved and that protein synthesis is essential for this regulation. Finally, we demonstrate that TOR signaling and cilia length are pivotal for a variety of downstream ciliary functions, such as cilia motility, fluid flow generation, and the establishment of left-right body asymmetry. Our findings reveal a unique role for the TOR pathway in regulating cilia size through protein synthesis and suggest that appropriate and defined lengths are necessary for proper function of the cilium.
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Shiaulou
S
Yuan
Jade
J
Li
Dennis R
DR
Diener
Michael A
MA
Choma
Joel L
JL
Rosenbaum
Zhaoxia
Z
Sun
D000818:Animals; D019521:Body Patterning; D002923:Cilia / Q000201:enzymology / Q000378:metabolism*; D019143:Evolution, Molecular; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009068:Movement; D009929:Organ Size; D014176:Protein Biosynthesis; D012212:Rheology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
C571017:Torc1 protein complex, zebrafish; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D019893:Ribosomal Protein S6 Kinases; D038362:Glycogen Synthase Kinase 3