Collective effects of cell cleavage dynamics

Abstract

A conserved process of early embryonic development in metazoans is the reductive cell divisions following oocyte fertilization, termed cell cleavages. Cell cleavage cycles usually start synchronously, lengthen differentially between the embryonic cells becoming asynchronous, and cease before major morphogenetic events, such as germ layer formation and gastrulation. Despite exhibiting species-specific characteristics, the regulation of cell cleavage dynamics comes down to common controllers acting mostly at the single cell/nucleus level, such as nucleus-to-cytoplasmic ratio and zygotic genome activation. Remarkably, recent work has linked cell cleavage dynamics to the emergence of collective behavior during embryogenesis, including pattern formation and changes in embryo-scale mechanics, raising the question how single-cell controllers coordinate embryo-scale processes. In this review, we summarize studies across species where an association between cell cleavages and collective behavior was made, discuss the underlying mechanisms, and propose that cell-to-cell variability in cell cleavage dynamics can serve as a mechanism of long-range coordination in developing embryos.

Keywords: cell cleavage; cell cycle; collective behavior and dynamics; embryogenesis; synchrony; tissue morphogenesis; variability.

FIGURE 1

Cell cycle length regulation from single cells to tissues in early cleaving embryos. (A) Single-cell cycle length is regulated by internal biochemical processes including CDK/cyclins oscillations, N/C ratio, zygotic genome activation and maternal mRNA regulation (Section 2.1). At the same time it impacts cell physical properties such as cytoskeletal mechanics and cell size. (B) Within a cell population the cell’s microenvironment can influence cell cycle length depending on the form of cell-cell communication (cytoplasmic bridges and diffusion of the cell cycle oscillators) and on changes in cell adhesion and cell shape occurring during mitotic rounding, resulting in variability in cell-to-cell cycle lengths (Section 2.2). (C) This cell cycle variability can generate further variability in other cell properties (cell size, shape) and impact collective tissue properties, such as topology and deformability (Section 2.3).

FIGURE 2

Cellular control mechanisms of cell cycle length changes during embryogenesis. (A) Cellular mechanisms regulating the cell cycle length involve the regulation of the concentration of nuclear and cytoplasmic factors and their interplay. Positive effect arrows indicate mechanisms that promote cell cleavages, whereas negative effect arrows indicate mechanisms that delay cell cleavages, thus lengthen the cell cycle. The depicted effects on cell cycle progression have been summarized from various organisms and may not apply for all systems, see text for details. Inset: diagram of mitosis control through Cdk1. Before mitosis, Cdk1 is under inhibition of checkpoint kinase 1 (Chk1) and protein phosphatase 1 (PP1). Mitotic entry is enabled by the Cdk1-cyclinB auto-amplification loop that inhibits its antagonists (Wee1, Myt, PP1) and activates its activator Cdc25. Mitosis exit is enabled by decreased Cdk1-CyclinB activity due to activation of APC/C and PP1. (B) The ratio of nuclear to cytoplasmic volume changes throughout cleavage divisions, leading to the titration of cytoplasmic against nuclear components. The right graph shows the negative correlation of cell size and cell cycle length of the AB lineage in early C. elegans development (Arata et al., 2014). (C) Zygotic transcription may influence the cell cycle directly or indirectly through cell fate while cell cycle length also influences transcriptional potential. (D) Maternal mRNA translation and degradation affects the availability of cell cycle regulators and thus the cell cycle length. These processes are regulated through modifications, such as polyadenylation and methylation, by RNA binding proteins.

FIGURE 3

Different ways to create cell cycle differences in a multinucleated or multicellular system. (A) Self-organized cell cycle duration and mitotic entry via local nuclear density and an example in the (A′) Xenopus extract system. Cdk1 diffusion upon nuclear envelope breakdown (red) triggers mitotic entry starting from a pacemaker nucleus in a low nucleus density region (after (Chang and Ferrell, 2013; Nolet et al., 2020)). (B) Cell size correlates negatively with cell cycle length in different species. This allows asymmetric divisions to set up cell cycle length differences in a tissue (B′) e.g., in the C. elegans embryo, asymmetric divisions lead to larger anterior cells with shorter cell cycles, resulting in a division wave throughout the embryo (Deppe et al., 1978). (C) Fate-dependent transcription factors may control the expression of cell cycle regulators, resulting in cell cycle length regulation and mitotic domains according to cell differentiation. (C′) In the ascidian Ciona intestinalis, the transcription factors GATA and AP-2 have been suggested to control Cdc25 expression along the anterior-posterior axis. This causes a gradient in G2-phase that compensates for a S-phase gradient, leading to equal cell cycle length throughout the embryo and mitotic synchrony (Ogura et al., 2011; Ogura and Sasakura, 2017). [abbreviations: A anterior; P—posterior; TFs: transcription factors].

FIGURE 4

Collective effects of cell cleavage dynamics in systems with shared and compartmentalized cytoplasm. (A) In systems with shared cytoplasm, spatial patterns of contractility can be induced by pathways linking the cell cycle and actomyosin skeleton (pathway after (Bement et al., 2015; Basant and Glotzer, 2018; Deneke et al., 2019)). (B) For example, surface contraction waves are regulated by Cdk1-cyclinB dynamics in starfish oocytes (Bischof et al., 2017) (C) Cytoplasmic streams can result from PP1 induced cortical contractility upon its release from inhibition by Cdk1 at mitosis exit, as seen during early divisions in Drosophila (Deneke et al., 2019). (D) In multicellular systems, cell divisions cause rearrangement of cell-cell contacts due to mitotic rounding. (E) Homogeneous distribution of mitotic rounding enables uniform tissue fluidization (melting) in the zebrafish blastula (Petridou et al., 2019; 2021). (F) Mitotic synchrony has also been suggested to affect cell packing and downstream cellular fate in the early mouse embryo (Fabrèges et al., 2023).