Omnis cellular e cellula – all cells arise from pre-existing cells. This seemingly obvious tenet of cell theory was only formalized when, in 1841, the Polish embryologist Robert Remak boldly described forms of animal cell division when examining chick embryo red blood cell development. Later, in 1882, German biologist Walther Flemming sketched, for the first time, the morphological changes during cell division in salamander embryos as they divide. Deriving from the Greek mitos (“thread”), Flemming coined the term “mitosis”, noting how neatly some “thick” fibers – later recognized as chromosomes – were organized and segregated at the cell’s midplane during its division. More than a century of research has sought to elucidate this elegant process. How do chromosomes arise from the scaffolds of a resting nucleus? How do they segregate evenly to create two daughter cells? And how does a cell know when to kickstart this process? 

A major breakthrough came with the discovery of cyclin-dependent kinases (CDKs) and cyclins, molecules that control when cells replicate their DNA and divide. The CDK/cyclin complex was long thought to act as a master clock of the cell cycle. But with all scientific research, knowledge is never set in stone and even some long-standing paradigms can be refuted. A growing body of evidence suggests that a variety of cell cycle processes can cycle independently of CDK/cyclin activity, such as in centriole biogenesis [1-2], ATP/NADH metabolism [3], cellular growth [4], and transcription [5], amongst other sub-cellular events [6]. These recent advances have sparked the emerging concept of ‘autonomous clocks’. 

Autonomous clocks are timing mechanisms in organisms that operate at their own frequencies to regulate various cellular phenomena. In dividing cells, these clocks are synchronized by CDKs and cyclins to match the timing of cell divisions. Think of autonomous clocks as the intrinsic motors of metronomes driving their periodic ticking. Only when these metronomes are placed on a common platform balanced on cylinders, do they get “phase-locked” together to click in synchrony. Strikingly, Bakshi et. al. has now discovered yet another cellular process that runs autonomously – cytoplasmic divisions [7]. 

Usually, during cell division, the nucleus divides first, followed by the cytoplasm. However, Bakshi et al. observed that in fruit fly embryos, this sequence can sometimes go awry. Early in development, cells on the surface of fruit fly embryosundergo synchronized cycles of nuclear divisions and cytoplasmic furrowing before gastrulation, the last step in early fly development. To observe these cycles in living embryos, Bakshi et al. generated embryos that express fluorescently labelled versions of histones and myosin’s regulatory light chain to visualize nuclei and cytoplasmic compartments respectively. The authors noticed that in wild-type fly embryos, 20% of all cytoplasmic compartments formed cytoplasmic furrows before mitotic entry. This observation was contrary to textbook depictions that describe the initiation of cytokinesis as strictly happening after mitosis. Wondering if such divisions occur due to an early local activation of CDK/cyclin complexes, the authors altered CDK activity via genetic means. Remarkably, they found that the timing of such early cytoplasmic divisions cannot be modulated by CDK activity, suggesting that they are uncoupled from nuclear divisions. 

Remarkably, the authors also observed for ~3% of  blastoderm divisions that the cytoplasm can sustain rounds of divisions completely without nuclei. If they could still divide without nuclei where principal CDK/cyclins normally initiate mitosis, is CDK activity at all required for cytoplasmic divisions? Using a combination of double-stranded RNAs targeting against all mitotic cyclins, Bakshi et. al. could halt CDK activity and its associated nuclear divisions immediately after fertilization. Indeed, they found that cytoplasmic divisions can occur in cycles without the blastoderm nuclei nor detectable oscillations in CDK activity. As CDKs require de novo synthesis of new cyclins at every cell cycle, the authors wished to test if the molecular mechanism for early cytoplasmic divisions also required protein synthesis. Surprisingly, by inhibiting protein translation, they found that cytoplasmic division cycles continued to occur and is likely not required to trigger early divisions. 

These findings boldly point towards an autonomous cycle that may regulate the timing of cytokinesis. The next step is clear: what is the molecule(s) acting as a clock for cytoplasmic divisions? It will be exciting to see whether these unexpected findings from the little fly embryo hold true more broadly in cell biology.

References:
 

1.     Aydogan MG, Wainman A, Saurya S, Steinacker TL, Caballe A, Novak ZA, Baumbach J, Muschalik N, Raff JW. A homeostatic clock sets daughter centriole size in flies. J Cell Biol. 2018 Apr 2;217(4):1233-1248. doi: 10.1083/jcb.201801014. Epub 2018 Mar 2. PMID: 29500190; PMCID: PMC5881511. 

2.     Aydogan MG, Steinacker TL, Mofatteh M, Wilmott ZM, Zhou FY, Gartenmann L, Wainman A, Saurya S, Novak ZA, Wong SS, Goriely A, Boemo MA, Raff JW. An Autonomous Oscillation Times and Executes Centriole Biogenesis. Cell. 2020 Jun 25;181(7):1566-1581.e27. doi: 10.1016/j.cell.2020.05.018. Epub 2020 Jun 11. PMID: 32531200; PMCID: PMC7327525. 

3.     Özsezen S, Papagiannakis A, Chen H, Niebel B, Milias-Argeitis A, Heinemann M. Inference of the High-Level Interaction Topology between the Metabolic and Cell-Cycle Oscillators from Single-Cell Dynamics. Cell Syst. 2019 Oct 23;9(4):354-365.e6. doi: 10.1016/j.cels.2019.09.003. Epub 2019 Oct 9. PMID: 31606371. 

4.     Liu X, Oh S, Peshkin L, Kirschner MW. Computationally enhanced quantitative phase microscopy reveals autonomous oscillations in mammalian cell growth. Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27388-27399. doi: 10.1073/pnas.2002152117. Epub 2020 Oct 21. PMID: 33087574; PMCID: PMC7959529. 

5.     Cho CY, Kelliher CM, Haase SB. The cell-cycle transcriptional network generates and transmits a pulse of transcription once each cell cycle. Cell Cycle. 2019 Feb;18(4):363-378. doi: 10.1080/15384101.2019.1570655. Epub 2019 Feb 5. PMID: 30668223; PMCID: PMC6422481. 

6.     Mofatteh M, Echegaray-Iturra F, Alamban A, Dalla Ricca F, Bakshi A, Aydogan MG. Autonomous clocks that regulate organelle biogenesis, cytoskeletal organization, and intracellular dynamics. Elife. 2021 Sep 29;10:e72104. doi: 10.7554/eLife.72104. PMID: 34586070; PMCID: PMC8480978. 

7.     Bakshi A, Iturra FE, Alamban A, Rosas-Salvans M, Dumont S, Aydogan MG. Cytoplasmic division cycles without the nucleus and mitotic CDK/cyclin complexes. Cell. 2023 Oct 12;186(21):4694-4709.e16. doi: 10.1016/j.cell.2023.09.010. PMID: 37832525; PMCID: PMC10659773.