Cilia at the Node of Mouse Embryos Sense Fluid Flow for Left-Right Determination via Pkd2

Yoshiba, Satoko; Shiratori, Hidetaka; Kuo, Ivana Y.; Kawasumi, Aiko; Shinohara, Kyosuke; Nonaka, Shigenori; Asai, Yasuko; Sasaki, Genta; Belo, José António; Sasaki, Hiroshi; Nakai, Junichi; Dworniczak, Bernd; Ehrlich, Barbara E.; Pennekamp, Petra; Hamada, Hiroshi

doi:10.1126/science.1222538

Cited by 266 publications

(325 citation statements)

References 28 publications

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“…A link between ciliary Ca 2+ signaling, the polycystin proteins, and cyst development has recently gained attention (42,(46)(47)(48)(49)(50)(51). The fact that the cilia in the InsP3R3 and PC2 knockdown cysts were still present, but absent in InsP3R1 knockdown cysts, by week 8, suggests that cilia may not be essential to the latter stages of cystogenesis and is broadly consistent with recent findings (52).…”

Section: Discussionsupporting

confidence: 81%

Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

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

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Mutations in polycystin 1 and 2 (PC1 and PC2) cause the common genetic kidney disorder autosomal dominant polycystic kidney disease (ADPKD). It is unknown how these mutations result in renal cysts, but dysregulation of calcium (Ca 2+ ) signaling is a known consequence of PC2 mutations. PC2 functions as a Ca 2+ -activated Ca 2+ channel of the endoplasmic reticulum. We hypothesize that Ca 2+ signaling through PC2, or other intracellular Ca 2+ channels such as the inositol 1,4,5-trisphosphate receptor (InsP3R), is necessary to maintain renal epithelial cell function and that disruption of the Ca 2+ signaling leads to renal cyst development. The cell line LLC-PK1 has traditionally been used for studying PKD-causing mutations and Ca 2+ signaling in 2D culture systems. We demonstrate that this cell line can be used in long-term (8 wk) 3D tissue culture systems. In 2D systems, knockdown of InsP3R results in decreased Ca 2+ transient signals that are rescued by overexpression of PC2. In 3D systems, knockdown of either PC2 or InsP3R leads to cyst formation, but knockdown of InsP3R type 1 (InsP3R1) generated the largest cysts. InsP3R1 and InsP3R3 are differentially localized in both mouse and human kidney, suggesting that regional disruption of Ca 2+ signaling contributes to cystogenesis. All cysts had intact cilia 2 wk after starting 3D culture, but the cells with InsP3R1 knockdown lost cilia as the cysts grew. Studies combining 2D and 3D cell culture systems will assist in understanding how mutations in PC2 that confer altered Ca 2+ signaling lead to ADPKD cysts. primary cilia | polycysin 2 | calcium release T he commonly occurring genetic kidney disorder, autosomal dominant polycystic kidney disease (ADPKD), is the result of mutations in polycystin 1 or 2 (PC1 or PC2). The progressive cyst formation within all segments of the nephron that defines the disorder leads to renal failure requiring treatment by dialysis and/or organ transplantation (1-3). Altered Ca 2+ signaling is one of several pathways that have been implicated in the disease (4, 5). A major limitation toward elucidating the role of Ca 2+ signaling in cyst formation has been the lack of easily manipulated, physiologically relevant experimental methodologies.In the past, ADPKD research has relied largely upon data from mouse models and cells maintained in 2D cell culture. Mouse models have played a significant role in understanding the biology of cyst formation but are unable to fully recapitulate the physiology of disease progression in humans due to the inherent differences between the species including life span, genetics, and environment. Two-dimensional cell culture has the ability to provide information on signaling pathways and response to therapies in a fast, high-throughput manner, but is incapable of replicating the inherent 3D nature of cyst formation. Advances in 3D tissue culture over the past 2 decades have improved the ability to model cyst development in vitro. However, previously published 3D tissue models of ADPKD have relied upon shortter...

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Section: Discussionsupporting

confidence: 81%

Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

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

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“…117 A third model suggests that the nodal flow initiates a Ca 2+ influx in crown cells on the left side of the node, via activation of the polycystins (PC2 and the PC1 homolog, PC1 like 1) in mechanosensory, immotile primary cilia. 7,9,118,119 In support of the latter model, the asymmetric expression of Ablim1 at the node during the mid-headfold stage requires both a nodal flow and PC2, but the details of this relationship have not been resolved. 114 Further, it was recently shown that glycosylation of the Notch receptor in the crown cells by the N-acetylgalactosamine-type O-glycosylation enzyme GALNT11 is essential for the optimal ratio between motile and immotile cilia at the mouse node, in addition to correct Pitx2 expression in Xenopus embryos.…”

Section: Nodal Cilia and Heterotaxymentioning

confidence: 99%

Cilia and coordination of signaling networks during heart development

et al. 2013

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“…People with leftright situs inversus of the viscera are reported to have similar rates of left-lateralised language dominance to people with normally patterned viscera (Tanaka et al, 1999). Visceral asymmetry appears to arise as a consequence of the homochirality (biased handedness) of amino acid molecules in living systems, that together create 'handed' cilia leading to a unidirectional, leftward fluid flow within the embryonic node Takaoka, Yamamoto, & Hamada, 2007;Yoshiba et al, 2012), and ultimately to different gene expression cascades on the two sides of the body. Human CNS asymmetries may also arise from analogous molecular/biophysical asymmetries, but the core mechanism is unknown.…”

mentioning

confidence: 99%

Asymmetry within and around the human planum temporale is sexually dimorphic and influenced by genes involved in steroid hormone receptor activity

Guadalupe

Zwiers

Wittfeld

et al. 2015

Cortex

118

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The genetic determinants of cerebral asymmetries are unknown. Sex differences in asymmetry of the planum temporale, that overlaps Wernicke’s classical language area, have been inconsistently reported. Meta-analysis of previous studies has suggested that publication bias established this sex difference in the literature. Using probabilistic definitions of cortical regions we screened over the cerebral cortex for sexual dimorphisms of asymmetry in 2337 healthy subjects, and found the planum temporale to show the strongest sex-linked asymmetry of all regions, which was supported by two further datasets, and also by analysis with the Freesurfer package that performs automated parcellation of cerebral cortical regions. We performed a genome-wide association scan meta-analysis of planum temporale asymmetry in a pooled sample of 3095 subjects, followed by a candidate-driven approach which measured a significant enrichment of association in genes of the ´steroid hormone receptor activity´ and 'steroid metabolic process' pathways. Variants in the genes and pathways identified may affect the role of the planum temporale in language cognition

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Cilia at the Node of Mouse Embryos Sense Fluid Flow for Left-Right Determination via Pkd2

Cited by 266 publications

References 28 publications

Cyst formation following disruption of intracellular calcium signaling

Cyst formation following disruption of intracellular calcium signaling

Cilia and coordination of signaling networks during heart development

Asymmetry within and around the human planum temporale is sexually dimorphic and influenced by genes involved in steroid hormone receptor activity

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