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Temperature-Induced Uncoupling of Cell Cycle Regulators

Hanieh Falahati, Woonyung Hur, Stefano Di Talia, Eric F. Wieschaus

Preprint posted on 11 February 2020 https://www.biorxiv.org/content/10.1101/2020.02.11.943266v1

Article now published in Developmental Biology at http://dx.doi.org/10.1016/j.ydbio.2020.11.010

Heating things up: altering temperature gives insight into cell cycle regulation. By using a thermofluidic channel to image fly embryos, Falahati et al., show that the cell cycle master regulator, Cdk1, may not be alone after all.

Selected by Berrak Ugur

Background

The cell cycle is a tightly regulated process that depends on specific timing and coordination of multiple steps. These steps are linked to each other through feedback loops. Although there has been extensive research on cell cycle regulation, understanding how each component contributes to an individual step has been challenging. A well-studied actor of cell cycle is cyclin dependent kinase 1 (cdk1) (Malumbres, 2014). Cdk1 in fly embryos act in waves to synchronize multiple divisions and is widely known as the master regulator of cell cycle (Deneke et al., 2016). Cdk1 activity regulates transitions between different steps of mitosis (prophase, prometaphase, metaphase, anaphase, and telophase). However, it is not well known if the mitotic transitions are strictly controlled by Cdk1 or coupled actions of various enzymes.

Key Findings

To study how cell cycle is regulated in early D. melanogaster embryos, Falahati et al. take advantage of a very simple idea of altering temperature in developing fly embryos. According to the Arrhenius equation, the reaction rates of an enzyme depends on temperature (Arrhenius, 1915). Therefore, if a single kinase like Cdk1 is regulating cell cycle, then the variables in reaction rate should change in similar trends as the temperature shifts. However, if multiple enzymes regulate cell cycle order, then the variables in reaction rate may change in different trends.

Figure 1: A schematic of the microfluidic device.  used for controling the temperature. a1 and a2 are used to push the fluid into the channels to two different temperatures. b1 and b2 are connected to the thermometer for readout of the flow temperature. c and d assure the continuity of the fluid passing over the embryos. Fly embryos are live-imaged using this device. https://doi.org/10.1101/2020.02.11.943266

The first 13 divisions in Drosophila embryos are highly synchronous (Rabinowitz, 1941). To test how temperature affects the cell cycle, the authors perform live imaging during a single division step in Drosophila embryos in a microfluidic device where they can precisely control temperature of the chamber between 5-35°C (Fig1). The authors show that there is no change in characteristics of each cell cycle step between 7-22°C, including chromatin structure, microtubule and centrosome organization. Next, they examine whether changes in temperature alter the rate of nuclear cycle in agreement with Arrhenius equation. Indeed, as previously reported in C. elegans and D. melanogaster (Begasse et al., 2015; Kuntz and Eisen, 2014), they show that nuclear cycle 11 rate also depends on Arrhenius equation. However, Arrhenius plots show that temperature response in prophase is especially prolonged at low temperature compared to other cell cycle stages. This observation, they claim, may indicate that (1) prometaphase entry is regulated by a highly temperature sensitive enzyme and (2) the aforementioned enzyme is not solely responsible for regulating earlier nuclear cycle events. To test if this sensitive enzyme is indeed Cdk1, the authors characterize Cdk1 activity at different temperatures during nuclear cycle 11. For this purpose, they use a Cdk1 sensor in flies and show that Cdk1 only becomes active before prometaphase but not earlier cell cycle steps at low temperature (7°C), consistent with their predictions. Overall, by using temperature shifts, Falahati et al. claim that Cdk1 may have other partners in the regulation of cell cycle steps before prophase.

Take home messages

  • Altering temperature by +/- 10° C does not change the characteristics of cell cycle steps but alters their duration in nuclear cycle 11 in Drosophila
  • Different cell cycle steps show specific Arrhenius equation dependencies
  • Prometaphase is more sensitive to temperature fluctuation compared to other cell cycle steps
  • Early cell cycle events before prometaphase (e.g. chromosome condensation and centrosome cycle) can occur independently of Cdk1 activity

What I liked about this study: I think that this preprint to provides a very neat trick to solve complex feedback loops. It is a good example of how we can combine physical properties of enzyme kinetics to study biological processes (Disclaimer: currently, Dr. Falahati and I work in the same laboratory, but the highlighted preprint is in a completely different field than both of our current studies)

Remaining Questions

1) It is interesting that a huge variance in temperature does not affect cell cycle timing, is it a specific phenomenon observed in flies?

2) You speculate that the steps earlier than prometaphase may be dependent on Polo or Aurora kinases. Do you plan to test the activation of these enzymes at varying temperatures?

3) Have you tested other nuclear cycles other than 11? Is there any possibility that this phenomenon that you observed with Cdk1 is only applicable to NC11?

4) How does your observation fits into literature on mammalian Cdk1?

 References

Arrhenius, S., 1915. Quantitative laws in biological chemistry /. G. Bell, London : https://doi.org/10.5962/bhl.title.4661

Begasse, M.L., Leaver, M., Vazquez, F., Grill, S.W., Hyman, A.A., 2015. Temperature Dependence of Cell Division Timing Accounts for a Shift in the Thermal Limits of C. elegans and C. briggsae. Cell Rep. 10, 647–653. https://doi.org/10.1016/j.celrep.2015.01.006

Deneke, V.E., Melbinger, A., Vergassola, M., Di Talia, S., 2016. Waves of Cdk1 Activity in S Phase Synchronize the Cell Cycle in Drosophila Embryos. Dev. Cell 38, 399–412. https://doi.org/10.1016/j.devcel.2016.07.023

Kuntz, S.G., Eisen, M.B., 2014. Drosophila embryogenesis scales uniformly across temperature in developmentally diverse species. PLoS Genet. 10, e1004293. https://doi.org/10.1371/journal.pgen.1004293

Malumbres, M., 2014. Cyclin-dependent kinases. Genome Biol. 15, 122. https://doi.org/10.1186/gb4184

Rabinowitz, M., 1941. Studies on the cytology and early embryology of the egg of Drosophila melanogaster. J. Morphol. 69, 1–49. https://doi.org/10.1002/jmor.1050690102

Tags: cell cycle, cyclin, prometaphase

Posted on: 6 May 2020

doi: https://doi.org/10.1242/prelights.18593

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