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Frequency and amplitude control of cortical oscillations by phosphoinositide waves

Nature Chemical Biology volume 12, pages 159–166 (2016)Cite this article

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A Corrigendum to this article was published on 18 March 2016

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Abstract

Rhythmicity is prevalent in the cortical dynamics of diverse single and multicellular systems. Current models of cortical oscillations focus primarily on cytoskeleton-based feedbacks, but information on signals upstream of the actin cytoskeleton is limited. In addition, inhibitory mechanisms—especially local inhibitory mechanisms, which ensure proper spatial and kinetic controls of activation—are not well understood. Here, we identified two phosphoinositide phosphatases, synaptojanin 2 and SHIP1, that function in periodic traveling waves of rat basophilic leukemia (RBL) mast cells. The local, phase-shifted activation of lipid phosphatases generates sequential waves of phosphoinositides. By acutely perturbing phosphoinositide composition using optogenetic methods, we showed that pulses of PtdIns(4,5)P2 regulate the amplitude of cyclic membrane waves while PtdIns(3,4)P2 sets the frequency. Collectively, these data suggest that the spatiotemporal dynamics of lipid metabolism have a key role in governing cortical oscillations and reveal how phosphatidylinositol 3-kinases (PI3K) activity could be frequency-encoded by a phosphatase-dependent inhibitory reaction.

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Figure 1: 5-phosphatases SHIP1 and synaptojanin 2 are required for wave dynamics.
Figure 2: Modulation of oscillation amplitude by PtdIns(4,5)P2.
Figure 3: Tuning oscillation cycle time by PI3K activity.
Figure 4: PI3Kδ is the main functional PI3K for oscillatory traveling waves.
Figure 5: PtdIns(3,4)P2, but not PtdIns(3,4,5)P3, is the timer of cortical oscillations.

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Change history

  • 11 February 2016

    In the version of this article initially published online, the name of author Qingsong Lin was misspelled as Qinsong Lin. The error has been corrected for the PDF and HTML versions of this article.

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Acknowledgements

We thank P. De Camilli for inspiring this project and for valuable discussions and E. Feng and L. Cheung for technical assistance. This work was supported by the National Research Foundation (NRF) Singapore under its NRF Fellowship Program (M.W., NRF Award No. NRF-NRFF2011-09) and Mechanobiology Institute at National University of Singapore.

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Authors and Affiliations

  1. Mechanobiology Institute, National University of Singapore, Singapore

    Ding Xiong & Min Wu

  2. Department of Biological Sciences, National University of Singapore, Singapore

    Ding Xiong, Shengping Xiao, Su Guo, Qingsong Lin & Min Wu

  3. Centre for Bioimaging Sciences, National University of Singapore, Singapore

    Ding Xiong, Shengping Xiao, Su Guo & Min Wu

  4. Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

    Fubito Nakatsu

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Contributions

M.W. and D.X. designed the experiments. D.X. performed the experiments and data analysis. S.X. assisted with imaging experiments and performed biochemistry experiments. Q.L. carried out mass spectrometry. S.G. and F.N. generated and tested reagents. M.W. and D.X. interpreted results and wrote the manuscript.

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Correspondence to Min Wu.

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Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–8. (PDF 0 kb)

Two-color TIRFM movie of cell coexpressing mCherry-SHIP1 (left) and FBP17-EGFP (middle) showing traveling waves.

SHIP1 waves (magenta) correlate with but lag behind FBP17 waves (green) in the merged view (right). The movie was acquired after antigen stimulation at 1 sec interval and plays at 15 frames per sec (15x real time). Scale bar: 5 μm. (AVI 5942 kb)

Two-color TIRFM movie of cell showing traveling waves of synaptojanin 2–mCherry (left) and FBP17-EGFP (middle)

Synaptojanin 2 waves (magenta) precisely overlap with FBP17 waves (green) in the merged panel (right). The movie was acquired after antigen stimulation at 2 sec intevals and plays at 7.5 frames per sec (15x real time). Scale bar: 5 μm. (AVI 3898 kb)

Three-color TIRFM movie of cell expressing FBP17-EGFP (left) and PI(4,5)P2-specific sensor (iRFP-PHPLCδ) (middle) showing traveling wave.

Wave is absent with cytosol marker mCherry-C1 (right). The movie was acquired after antigen stimulation at 2 sec intevals and plays at 30 frames per sec (60x real time). Scale bar: 5 μm. (AVI 7293 kb)

TIRFM movie of cells expressing FBP17-EGFP showing conversion of irregular pattern to regular recurring traveling waves by the addition of low dose wortmannin (0.5 μM).

The movie was acquired after antigen stimulation at 2 sec intervals and plays at 30 frames per sec (60x real time). Scale bar: 5 μm. (AVI 6185 kb)

TIRFM movie of cells expressing FBP17-EGFP shows increase in oscillation cycle time upon sequential treatment with 0.5 μM and 1 μM wortmannin.

The movie was acquired after antigen stimulation at 2 sec intervals and plays at 30 frames per sec (60x real time). Scale bar: 5 μm. (AVI 10363 kb)

Two-color TIRFM movie of cell coexpressing PI(3,4,5)P3-specific sensor (mCherry-PHGrp1) (left) and FBP17-EGFP (right).

Traveling wave of PI(3,4,5)P3 becomes much more obvious after addition of low dose wortmannin (0.5 μM). The movie was acquired after antigen stimulation at 2 sec intervals and plays at 30 frames per sec (60x real time). Scale bar: 5 μm. (AVI 6723 kb)

Two-color TIRFM movie of cell coexpressing PI(3,4)P2-specific sensor (RFP-PHTAPP1) (left) and FBP17-EGFP (right) showing traveling wave.

PI(3,4)P2 wave is phase-shifted compared to that of FBP17. The movie was acquired after antigen stimulation at 2 sec intervals and plays at 30 frames per sec (60x real time). Scale bar: 5 μm. (AVI 1180 kb)

Two-color TIRFM movie of mast cell coexpressing Tks5-EGFP (left) and mCherry-CIP4 (middle) showing traveling wave.

SHIP1 waves (magenta) correlate with but lag behind CIP4 waves (green) in the merged view (right). The movie was acquired after antigen stimulation at 0.5 sec intervals and plays at 30 frames per sec (15x real time). Scale bar: 5 μm. (AVI 8179 kb)

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Xiong, D., Xiao, S., Guo, S. et al. Frequency and amplitude control of cortical oscillations by phosphoinositide waves. Nat Chem Biol 12, 159–166 (2016). https://doi.org/10.1038/nchembio.2000

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