Intraciliary calcium oscillations initiate vertebrate left-right asymmetry

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Summary

Background

Bilateral symmetry during vertebrate development is broken at the left-right organizer (LRO) by ciliary motility and the resultant directional flow of extracellular fluid. However, how ciliary motility is perceived and transduced into asymmetrical intracellular signaling at the LRO remains controversial. Previous work has indicated that sensory cilia and polycystin-2 (Pkd2), a cation channel, are required for sensing ciliary motility, yet their function and the molecular mechanism linking both to left-right signaling cascades is unknown.

Results

Here, we report novel intraciliary calcium oscillations (ICOs) at the LRO that connect ciliary sensation of ciliary motility to downstream left-right signaling. Utilizing cilia-targeted genetically-encoded calcium indicators in live zebrafish embryos, we show that ICOs depend on Pkd2 and are left-biased at the LRO in response to ciliary motility. Asymmetric ICOs occur with onset of LRO ciliary motility, thus representing the earliest known LR asymmetric molecular signal. Suppression of ICOs using a cilia-targeted calcium sink demonstrates that they are essential for LR development.

Conclusions

These findings demonstrate that intraciliary calcium initiates LR development and identify cilia as a functional ion signaling compartment connecting ciliary motility and flow to molecular LR signaling.

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Most cited references 46

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Optimization of a GCaMP calcium indicator for neural activity imaging.

Jasper Akerboom, Tsai-Wen Chen, Trevor J. Wardill … (2012)

Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Recent efforts in protein engineering have significantly increased the performance of GECIs. The state-of-the art single-wavelength GECI, GCaMP3, has been deployed in a number of model organisms and can reliably detect three or more action potentials in short bursts in several systems in vivo. Through protein structure determination, targeted mutagenesis, high-throughput screening, and a battery of in vitro assays, we have increased the dynamic range of GCaMP3 by severalfold, creating a family of "GCaMP5" sensors. We tested GCaMP5s in several systems: cultured neurons and astrocytes, mouse retina, and in vivo in Caenorhabditis chemosensory neurons, Drosophila larval neuromuscular junction and adult antennal lobe, zebrafish retina and tectum, and mouse visual cortex. Signal-to-noise ratio was improved by at least 2- to 3-fold. In the visual cortex, two GCaMP5 variants detected twice as many visual stimulus-responsive cells as GCaMP3. By combining in vivo imaging with electrophysiology we show that GCaMP5 fluorescence provides a more reliable measure of neuronal activity than its predecessor GCaMP3. GCaMP5 allows more sensitive detection of neural activity in vivo and may find widespread applications for cellular imaging in general.

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Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.

Shigenori Nonaka, Yosuke Tanaka, Yasushi Okada … (1998)

Microtubule-dependent motor, murine KIF3B, was disrupted by gene targeting. The null mutants did not survive beyond midgestation, exhibiting growth retardation, pericardial sac ballooning, and neural tube disorganization. Prominently, the left-right asymmetry was randomized in the heart loop and the direction of embryonic turning. lefty-2 expression was either bilateral or absent. Furthermore, the node lacked monocilia while the basal bodies were present. Immunocytochemistry revealed KIF3B localization in wild-type nodal cilia. Video microscopy showed that these cilia were motile and generated a leftward flow. These data suggest that KIF3B is essential for the left-right determination through intraciliary transportation of materials for ciliogenesis of motile primary cilia that could produce a gradient of putative morphogen along the left-right axis in the node.

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Calcium oscillations increase the efficiency and specificity of gene expression.

R Dolmetsch, K. Xu, R Lewis (1998)

Cytosolic calcium ([Ca2+]i) oscillations are a nearly universal mode of signalling in excitable and non-excitable cells. Although Ca2+ is known to mediate a diverse array of cell functions, it is not known whether oscillations contribute to the efficiency or specificity of signalling or are merely an inevitable consequence of the feedback control of [Ca2+]i. We have developed a Ca2+ clamp technique to investigate the roles of oscillation amplitude and frequency in regulating gene expression driven by the proinflammatory transcription factors NF-AT, Oct/OAP and NF-kappaB. Here we report that oscillations reduce the effective Ca2+ threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation. In addition, specificity is encoded by the oscillation frequency: rapid oscillations stimulate all three transcription factors, whereas infrequent oscillations activate only NF-kappaB. The genes encoding the cytokines interleukin (IL)-2 and IL-8 are also frequency-sensitive in a way that reflects their degree of dependence on NF-AT versus NF-kappaB. Our results provide direct evidence that [Ca2+]i oscillations increase both the efficacy and the information content of Ca2+ signals that lead to gene expression and cell differentiation.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9107782

Journal ID (pubmed-jr-id): 8548

Journal ID (nlm-ta): Curr Biol

Journal ID (iso-abbrev): Curr. Biol.

Title: Current biology : CB

ISSN (Print): 0960-9822

ISSN (Electronic): 1879-0445

Publication date Nihms-submitted: 6 June 2015

Publication date (Electronic): 05 February 2015

Publication date (Print): 2 March 2015

Publication date PMC-release: 02 March 2016

Volume: 25

Issue: 5

Pages: 556-567

Affiliations

[1 ]Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA

[2 ]Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA

Author notes

[# ]Correspondence and request for materials should be addressed to: martina.brueckner@ 123456yale.edu and zhaoxia.sun@ 123456yale.edu

[3]

Current address: School of Public Health, School of Medicine, Zhejiang University, Hangzhou, 310058, China

[*]

These authors contributed equally

Article

Manuscript ID: NIHMS661880

DOI: 10.1016/j.cub.2014.12.051

PMC ID: 4469357

PubMed ID: 25660539

SO-VID: 478928ab-907c-43eb-921e-a4b1a39382d5

License:

This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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Intraciliary calcium oscillations initiate vertebrate left-right asymmetry

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Summary

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Graphical Abstract

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Neuronal Signaling

Most cited references 46

Optimization of a GCaMP calcium indicator for neural activity imaging.

Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.

Calcium oscillations increase the efficiency and specificity of gene expression.

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