DGKδ triggers endoplasmic reticulum release of IFT88-containing vesicles destined for the assembly of primary cilia

Ding, Jie; Shao, Lei; Yao, Ye; Tong, Xin; Liu, Huaize; Shen, Ya; Xie, Lu; Cheng, Steven Y.

doi:10.1038/s41598-017-05680-8

Cited by 15 publications

(12 citation statements)

References 55 publications

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“…For example, one of the first identified ciliopathies is the result of a mutation in the gene Ift88/Polaris . Ift88 is a protein that is transported within ciliary vesicles to facilitate ciliary biogenesis [4,5]. Loss of Ift88 leads to cystic kidney disease in both mouse and human [6,7].…”

Section: Introductionmentioning

confidence: 99%

Divergent roles of the Wnt/PCP Formin Daam1 in renal ciliogenesis

et al. 2019

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Kidneys are composed of numerous ciliated epithelial tubules called nephrons. Each nephron functions to reabsorb nutrients and concentrate waste products into urine. Defects in primary cilia are associated with abnormal formation of nephrons and cyst formation in a wide range of kidney disorders. Previous work in Xenopus laevis and zebrafish embryos established that loss of components that make up the Wnt/PCP pathway, Daam1 and ArhGEF19 (wGEF) perturb kidney tubulogenesis. Dishevelled, which activates both the canonical and non-canonical Wnt/PCP pathway, affect cilia formation in multiciliated cells. In this study, we investigated the role of the noncanoncial Wnt/PCP components Daam1 and ArhGEF19 (wGEF) in renal ciliogenesis utilizing polarized mammalian kidney epithelia cells (MDCKII and IMCD3) and Xenopus laevis embryonic kidney. We demonstrate that knockdown of Daam1 and ArhGEF19 in MDCKII and IMCD3 cells leads to loss of cilia, and Daam1’s effect on ciliogenesis is mediated by the formin-activity of Daam1. Moreover, Daam1 co-localizes with the ciliary transport protein Ift88 and is present in cilia. Interestingly, knocking down Daam1 in Xenopus kidney does not lead to loss of cilia. These data suggests a new role for Daam1 in the formation of primary cilia.

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Section: Introductionmentioning

confidence: 99%

Divergent roles of the Wnt/PCP Formin Daam1 in renal ciliogenesis

et al. 2019

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“…WDR35 did not localize in the Golgi (data not shown). Ding et al () reported that IFT88, a primary cilium protein, localizes in the ER and plays roles in the movement of IFT88‐containing COPII vesicles from the ER exit sites to primary cilia (Ding et al, ). Thus, we determined whether WDR35 was also localized in the ER.…”

Section: Resultsmentioning

confidence: 99%

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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“…Because vesicles are involved in cilium biogenesis, localization studies were carried out to determine whether Daam1 puncta are vesicles that carry ciliary components. A mCherry-Daam1 construct was co-transfected with an IFT88-GFP construct (Ding et al , 2017). Daam1 localizes to vesicles that carry IFT88 (Figure 4B, S1C).…”

Section: Resultsmentioning

confidence: 99%

“…Although ciliopathies can manifest in a number of different ways, the vast majority of ciliopathies result in kidney abnormalities (Arts and Knoers, 2013). For example, one of the first described ciliopathies is the result of a mutation in the gene IFT88 / Polaris, a protein is transported within vesicles to facilitate ciliary biogenesis (Yoder et al , 2002; Ding et al , 2017). Loss of IFT88 leads to cystic kidney disease in both mouse and human (Moyer et al , 1994; Onuchic et al , 1995).…”

Section: Introductionmentioning

confidence: 99%

The Role of the Wnt/PCP Formin Daam1 in Renal Ciliogenesis

Krneta-Stankic

Kloc

et al. 2019

Preprint

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16Kidneys are composed of numerous ciliated epithelial tubules called nephrons. Each nephron functions to reabsorb 17 nutrients and concentrate waste products into urine. Defects in primary cilia are associated with abnormal formation of 18 nephrons and cyst formation in a wide range of kidney disorders. Previous work in Xenopus laevis and zebrafish embryos 19 established that loss of components that make up the Wnt/PCP pathway, Daam1 and ArhGEF19 (wGEF) perturb kidney 20 tubulogenesis. Dishevelled, which activates both the canonical and non-canonical Wnt/PCP pathway, affect cilia 21 formation in multiciliated cells. In this study, we investigated the role of the noncanoncial Wnt/PCP components Daam1 22and ArhGEF19 (wGEF) in renal ciliogenesis utilizing polarized mammalian kidney epithelia cells (MDCKII and IMCD3) and 23Xenopus laevis embryonic kidney. We demonstrate that knockdown of Daam1 and ArhGEF19 in MDCKII and IMCD3 cells 24 leads to loss of cilia, and Daam1's effect on ciliogenesis is mediated by the formin-activity of Daam1. Moreover, Daam1 25 co-localizes with the ciliary transport protein IFT88. Interestingly, knocking down Daam1 in Xenopus kidney does not 26 lead to loss of cilia. This data suggests a new role for Daam1 in the formation of primary cilia. 27 catenin, the Wnt co-transcription factor, results in a reduction of cilia (Zhu et al., 2015). In mouse and Xenopus laevis a 39 protein called Chibby1, which functions to shuttle β-catenin out of the nucleus, localizes to the cilia and is required for 40 proper ciliogenesis and kidney development (Lee et al., 2014; Shi et al., 2014). Additionally, mutations in genes that 41 regulate cilia formation typically results in increased sensitivity to Wnt ligands, although the mechanism for this 42 phenomenon is heavily debated (Corbit et al., 2008). Moreover, Dishevelled, a component of both the canonical and 43 non-canonical Wnt pathway, is required for actin assembly and positioning of the basal bodies on the surface of the cell 44 during ciliogenesis in X. laevis multiciliated skin cells (Park et al., 2008). 45Actin filaments are important for proper ciliogenesis. In motile multiciliated cells, the cilia are connected by an actin 46 network (Werner et al., 2011). Although this actin network is not clearly visible around primary cilia, application of drugs 47

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DGKδ triggers endoplasmic reticulum release of IFT88-containing vesicles destined for the assembly of primary cilia

Cited by 15 publications

References 55 publications

Divergent roles of the Wnt/PCP Formin Daam1 in renal ciliogenesis

Divergent roles of the Wnt/PCP Formin Daam1 in renal ciliogenesis

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

The Role of the Wnt/PCP Formin Daam1 in Renal Ciliogenesis

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