Role for the IFT-A Complex in Selective Transport to the Primary Cilium

Fu, Wenxiang; Wang, Lei; Kim, Sehyun; Li, Ji; Dynlacht, Brian David

doi:10.1016/j.celrep.2016.10.018

Cited by 80 publications

(100 citation statements)

References 64 publications

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“…These correlations suggest that the different phenotypes might reflect differences in cilia assembly and function. In addition, a recent study showed selective cargo transport activity of WDR35 in regulating cilium assembly in human RPE1 cells (Fu et al, ). Further investigation of IFT particles and specific cargos would provide deeper insight into the mechanisms that dictate the effects on skeletogenesis among the skeletal ciliopathies.…”

Section: Discussionmentioning

confidence: 99%

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

et al. 2017

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Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes.The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

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Section: Discussionmentioning

confidence: 99%

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

et al. 2017

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“…Through a study of a series of truncating mutations, the minimal IFT121 regions required for binding to other complex components were determined [38]. Based on these data, the SRPS missense mutations identified here are predicted to interfere with IFT121 binding to core complex member IFT122 and the centrosomal protein 290-KD (Cep290).…”

Section: Discussionmentioning

confidence: 99%

Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia

Durán

Taylor

Zhang

et al. 2017

Cilia

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BackgroundSkeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function.ResultsHerein we describe mutations in IFT43, a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described IFT43 mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the IFT43 SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43.ConclusionsThis study defines a new IFT43-associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13630-017-0051-y) contains supplementary material, which is available to authorized users.

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“…WDR35 is also known as IFT121, a component of IFT‐A found in primary cilia (Behal et al, ; Blacque et al, ), where it plays roles in formation and is required for retrograde intraflagellar transport (Fu et al, ). Primary cilia formation is required for nutrient sensing and signal transduction induced by autophagy, which is negatively regulated by mTORC1 (Parmigiani et al, ; Tang et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…WDR35 has been implicated in multiple genetic diseases, including Sensenbrenner syndrome (Bacino, Dhar, Brunetti-Pierri, Lee, & Bonnen, 2012;Gilissen et al, 2010;Hoffer, Fryssira, Konstantinidou, Ropers, & Tzschach, 2013), short rib polydactyly syndromes (Mill et al, 2011) and Ellis-van Creveld syndrome (Caparros-Martin, Luca, & Cartault, 2015), which indicates that it plays important roles in development, although how it influences development has not been elucidated. In addition, the intraflagellar transport (IFT)-A complex containing WDR35 is involved in selective transport in primary cilia (Fu, Wang, Kim, Li, & Dynlacht, 2016). WDR35 expression is regulated through mechanisms, including AMPK, ROS and p38 MAPK phosphorylation (Tsunekawa et al, 2013).…”

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RagA, an mTORC1 activator, interacts with a hedgehog signaling protein, WDR35/IFT121

et al. 2019

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Small Ras‐like GTPases act as molecular switches for various signal transduction pathways. RagA, RagB/RagC and RagD are small Ras‐like GTPases that play regulatory roles in mTORC1. Lack of proper activation of mTORC1 can lead to diseases, such as cancer and diabetes. In this study, we found an interaction between RagA and WDR35. Mutations of WDR35 may cause genetic diseases including Sensenbrenner syndrome. WDR35 seems to be a hedgehog signaling protein with a possible ciliary function and a possible upstream regulator of RagA. RagB is a homologue of RagA and is also associated with WDR35. WDR35 is present in the endoplasmic reticulum, but usually not in lysosomes, where Rag family proteins act as an mTORC1 switch. Over‐expression of WDR35 results in decreased phosphorylation of ribosome S6 protein in a RagA‐, RagB‐ and RagC‐dependent manner. Thus, WDR35 is associated with RagA, RagB and RagC and might negatively influence mTORC1 activity.

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Role for the IFT-A Complex in Selective Transport to the Primary Cilium

Cited by 80 publications

References 64 publications

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia

RagA, an mTORC1 activator, interacts with a hedgehog signaling protein, WDR35/IFT121

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