ArticlePLoS genetics2016
Genetic Analysis Reveals a Hierarchy of Interactions between Polycystin-Encoding Genes and Genes Controlling Cilia Function during Left-Right Determination.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 64 citations in OpenAlex.
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- BMP4 regulates asymmetric Pkd2 distribution in mouse nodal immotile cilia and ciliary mechanosensing required for left-right determination.Developmental dynamics : an official publication of the American Association of Anatomists · 2025Article
- Review
- CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans.American journal of human genetics · 2025Article
- Breaking Left-Right Symmetry by the Interplay of Planar Cell Polarity, Calcium Signaling and Cilia.Cells · 2024Review
- Evolution of ion channels in cetaceans: a natural experiment in the tree of life.Scientific reports · 2024Article
- Emerging mechanistic understanding of cilia function in cellular signalling.Nature reviews. Molecular cell biology · 2024Review
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- Function of nodal cilia in left-right determination: Mechanical regulation in initiation of symmetry breaking.Biophysics and physicobiology · 2024Review
- Asthma exacerbations and eosinophilia in the UK Biobank: a genome-wide association study.ERJ open research · 2024Article
- Emerging principles of primary cilia dynamics in controlling tissue organization and function.The EMBO journal · 2023Review
- Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.Disease models & mechanisms · 2023Article
- Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.American journal of medical genetics. Part A · 2023Article
- Identification of novel compound heterozygous variants in theFrontiers in molecular biosciences · 2023Article
- Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases.Frontiers in genetics · 2022Article
- Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis.Frontiers in molecular biosciences · 2022Review
- NovelFrontiers in medicine · 2021Article
- Monoallelic Mutations inCirculation. Genomic and precision medicine · 2020Article
- A fully-automated method discovers loss of mouse-lethal and human-monogenic disease genes in 58 mammals.Nucleic acids research · 2020Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
During mammalian development, left-right (L-R) asymmetry is established by a cilia-driven leftward fluid flow within a midline embryonic cavity called the node. This 'nodal flow' is detected by peripherally-located crown cells that each assemble a primary cilium which contain the putative Ca2+ channel PKD2. The interaction of flow and crown cell cilia promotes left side-specific expression of Nodal in the lateral plate mesoderm (LPM). Whilst the PKD2-interacting protein PKD1L1 has also been implicated in L-R patterning, the underlying mechanism by which flow is detected and the genetic relationship between Polycystin function and asymmetric gene expression remains unknown. Here, we characterize a Pkd1l1 mutant line in which Nodal is activated bilaterally, suggesting that PKD1L1 is not required for LPM Nodal pathway activation per se, but rather to restrict Nodal to the left side downstream of nodal flow. Epistasis analysis shows that Pkd1l1 acts as an upstream genetic repressor of Pkd2. This study therefore provides a genetic pathway for the early stages of L-R determination. Moreover, using a system in which cultured cells are supplied artificial flow, we demonstrate that PKD1L1 is sufficient to mediate a Ca2+ signaling response after flow stimulation. Finally, we show that an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function; as such, destabilizing the domain causes L-R defects in the mouse. Our demonstration that PKD1L1 protein can mediate a response to flow coheres with a mechanosensation model of flow sensation in which the force of fluid flow drives asymmetric gene expression in the embryo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.