Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway

DiBella, Linda M.; Park, Alice; Sun, Zhaoxia

doi:10.1093/hmg/ddn384

Cited by 81 publications

(82 citation statements)

References 63 publications

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“…Interestingly, S6k1 OE also displayed long cilia and expanded lumens in the pronephric duct (Fig. S3 D-I and Tables S6 and S7), a phenotype commonly associated with ciliary defects (3,11). Similar to embryos with global overexpression of S6k1, chimeric DFC S6k1 OE embryos produced longer cilia in a dose-responsive manner ( Fig.…”

Section: Resultsmentioning

confidence: 82%

“…TORC1 influences cellular growth by phosphorylating ribosomal protein S6 kinase 1 (S6K1), a serine/threonine kinase that regulates S6 ribosomal protein and other members of the translational machinery (3,16). To assess whether S6k1 is required for Torc1-mediated cilia length control, we overactivated S6k1 by mRNA overexpression and analyzed for ciliary length defects.…”

Section: Resultsmentioning

confidence: 99%

“…Loss of tuberous sclerosis complex (TSC) proteins in zebrafish and mice result in cystic kidneys and abnormally long renal cilia (3,4). Additionally, proteins associated with Meckel-Gruber syndrome and retinitis pigmentosa also influence cilia length (5,6).…”

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confidence: 99%

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Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation

Yuan¹,

Li²,

Diener

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.Chlamydomonas | mammalian target of rapamycin | Kupffer's vesicle | laterality | flagella

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Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

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Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation

Yuan¹,

Li²,

Diener

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This hypothesis is supported by previous observations of hyper-responsiveness in lung-specific Atg7 knock-out mice with abnormal ciliogenesis and long cilia formation in mTORactivated cells. 103,104 Basal autophagy regulates the turnover of proteins involved in cilia function, thus controlling sensitivity of the cell to different stressors, such as cigarette smoking. Therefore, inhibition of autophagy in lung epithelial cells may have therapeutic relevance in COPD, chronic bronchitis or emphysema patients.…”

Section: Autophagy and Ciliummentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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“…Protruding from the cell into its environment, the cilium is involved in multiple signaling pathways, including the Sonic hedgehog (Shh) pathway, the Wnt pathways, and the target of rapamycin (TOR) pathway. [1][2][3][4][5] Not surprisingly, defects in the cilium have been linked to a growing list of human diseases, coined "ciliopathies," ranging from laterality defects, retinal degeneration, polycystic kidney disease (PKD), and other hepatorenal fibrocystic disorders to obesity and diabetes (for a review, see reference 6).…”

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confidence: 99%

Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell Polarity

Cao

Park

Sun

2010

Journal of the American Society of Nephrology

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The highly conserved intraflagellar transport (IFT) proteins are essential for cilia formation in multiple organisms, but surprisingly, cilia form in multiple zebrafish ift mutants. Here, we detected maternal deposition of ift gene products in zebrafish and found that ciliary assembly occurs only during early developmental stages, supporting the idea that maternal contribution of ift gene products masks the function of IFT proteins during initial development. In addition, the basal bodies in multiciliated cells of the pronephric duct in ift mutants were disorganized, with a pattern suggestive of defective planar cell polarity (PCP). Depletion of pk1, a core PCP component, similarly led to kidney cyst formation and basal body disorganization. Furthermore, we found that multiple ift genes genetically interact with pk1. Taken together, these data suggest that IFT proteins play a conserved role in cilia formation and planar cell polarity in zebrafish.

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Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway

Cited by 81 publications

References 63 publications

Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation

Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation

Autophagy and regulation of cilia function and assembly

Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell Polarity

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