Coordinating cell polarity and cell cycle progression: what can we learn from flies and worms?

Abstract

Spatio-temporal coordination of events during cell division is crucial for animal development. In recent years, emerging data have strengthened the notion that tight coupling of cell cycle progression and cell polarity in dividing cells is crucial for asymmetric cell division and ultimately for metazoan development. Although it is acknowledged that such coupling exists, the molecular mechanisms linking the cell cycle and cell polarity machineries are still under investigation. Key cell cycle regulators control cell polarity, and thus influence cell fate determination and/or differentiation, whereas some factors involved in cell polarity regulate cell cycle timing and proliferation potential. The scope of this review is to discuss the data linking cell polarity and cell cycle progression, and the importance of such coupling for asymmetric cell division. Because studies in model organisms such as Caenorhabditis elegans and Drosophila melanogaster have started to reveal the molecular mechanisms of this coordination, we will concentrate on these two systems. We review examples of molecular mechanisms suggesting a coupling between cell polarity and cell cycle progression.

Keywords: Caenorhabditis elegans; Drosophila melanogaster; cell cycle; cell polarity.

Figure 1.

Somatic and embryonic cell cycles and their regulation by cyclin/Cdk complexes. (a) Schematic of the cell cycle in somatic and early embryonic cells. DNA synthesis (S, blue), mitosis (M, red) and gap phases (G1, G2, green) are indicated. (b) Representation of the cyclin/Cdk complexes regulating the transition between cell cycle phases. The half moons outside the cell cycle represent the level of activity of the indicated complexes (based on studies performed in mammalian cells). Mammalian (black), Caenorhabditis elegans (brown) and Drosophila melanogaster (grey) homologues are shown. Components underlined and in bold indicate essential players for each model system (adapted from [9]).

Figure 2.

Coordination of cell polarity, cell fate and cell cycle progression in the early Caenorhabditis elegans embryo. (a) The top drawing shows a schematic of a one-cell embryo in mitosis (metaphase) with PAR-3, -6 and PKC-3 (blue) at the anterior, and PAR-1 and PAR-2 (blue), at the posterior cortex. The lower drawings are schematic of two-cell embryos showing the localization and levels of MEX-5 (dark green) and PIE-1 (light green), and the cell cycle regulators PLK-1 (red) and CDC-25 (red). The first asymmetric cell division generates a large anterior blastomere AB, which divides before the smaller posterior P1 blastomere. (b) A–P polarity cues and PAR proteins control the asymmetric localization of MEX-5, which directs PLK-1 localization (as indicated by arrows). SPAT-1 activates PLK-1 to promote earlier mitotic entry in the anterior blastomere. In turn, PLK-1 phosphorylates and activates MEX-5 (blue arrow). PLK-1 may also control polarity directly, by phosphorylating PAR proteins (PARs; dotted arrow). MEX-5 promotes proteasomal degradation of PIE-1 by CRL2^ZIF-1 in the somatic lineage (blue arrow). Red boxes indicate proteins with well-established function in cell cycle regulation, blue boxes indicate polarity proteins and green boxes indicate cell fate determinants, in this and other figures. Positive regulation indicated by arrows, negative regulation indicated by bars.

Figure 3.

Par1 regulates the asymmetric cell division of the male germ stem cell in Drosophila melanogaster. A cluster of supporting cells, called the HUB cells (in light grey), provides the niche that is essential for the maintenance of stem cell identity of the male germline stem cell. The mitotic spindle aligns towards the HUB cells, generating one daughter that remains close to the HUB cells and maintains stem cell identity, and one daughter far away from the HUB, which differentiates. Par1 (blue) and cyclin A (CycA, red) are part of a surveillance mechanism that localizes to the spectrosome (green) and prevents mitotic entry until proper orientation of the mitotic spindle is achieved.

Figure 4.

Asymmetric cell division of Drosophila melanogaster neuroblasts (NB) and sensory organ precursor (SOP) cells. (a) (i) After delamination from the layer of the epithelium, the NB divides asymmetrically to generate a new NB and a ganglion mother cell (GMC). Prospero (Pros, yellow) localizes as a crescent on the basal side of the NB and it is segregated to the GMC, where it accumulates in the nucleus. Nuclear Pros prevents the expression of cell cycle genes contributing to terminal differentiation of the GMC, which divides once to generate neuron and a glial cell. (ii) Schematic representation of the molecular links between cell cycle components (Polo, Aurora A) and cell fate determinants that contribute to the neuroblast asymmetric cell division. (b) Asymmetric division of the sensory organ precursor (SOP) cell of the Drosophila PNS, which gives rise to an anterior cell, pIIb and a posterior cell, pIIa. (i) Schematic of the link between Aurora A and Numb that contributes to the SOP asymmetric cell division. Numb (green) accumulates in the pIIB cell. pIIa generates one shaft cell and one socket cell, whereas pIIb generates a glial cell and pIIIb that produces a neuron and a sheat cell. Numb accumulates in pIIb and selectively segregates in some further progenies. (ii) Schematic of the link between Aurora A and Numb that contributes to the SOP asymmetric cell division.

Figure 5.

Molecular circuitry linking the cell cycle, cell fate and cell polarity machineries in Drosophila melanogaster and Caenorhabditis elegans. The pathways involved in D. melanogaster are on the top part of the figure, those in C. elegans on the bottom part. Drosophila melanogaster (grey), C. elegans (brown) and mammalian (black) homologues are indicated. Arrows and lines with the bar indicate positive and negative regulation, respectively. Dotted lines mean that the precise molecular mechanism between indicated proteins is not yet well understood; however, the genetic data suggest a crosstalk between these players.