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Published in final edited form as: Biochem Soc Trans. 2020 Jun 30;48(3):1243–1253. doi: 10.1042/BST20200298

Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

Sukriti Kapoor 1, Sachin Kotak 1,✉
PMCID: PMC7616972  EMSID: EMS88687  PMID: 32597472

Abstract

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e., anterior-posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This mis-regulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

Keywords: Centrosome, Aurora A kinase, Polarity establishment, Actomyosin network, PAR proteins, RhoGEF-ECT-2, C. elegans

Introduction

How a single cell polarizes itself to establish specialized domains that are critical for development and morphogenesis has intrigued scientists over the ages1–6. An initially indeterminate cell organizes its cellular components in an asymmetric, distinct manner, through a process known as cell polarization. The proper establishment of cell polarity ensures proper segregation of the cell fate determinants. Therefore, insights into the spatiotemporal mechanisms of polarity establishment is crucial to understand the fate and function of a cell and, eventually, the development of an organism. Because of the essential nature of this process for the origin and maintenance of life, dysregulation may cause developmental disorders and cancer7–16. Mechanisms of cell polarization are extensively studied in the context of several cellular models such as Drosophila oocytes and neuroblasts, asexual development of Volvox carteri, epithelial cells, and yeast3,5,6,17. However, in this mini-review we will mainly focus on our recent work and the work from three other groups that have reported the newly identified function of Aurora A kinase in polarity establishment in Caenorhabditis elegans one-cell embryo18–21.

Because of its large size and amenability to experimental manipulations, C. elegans one-cell embryo serves as an excellent model to study various fundamental processes, including polarity establishment. The one-cell embryo polarizes soon after fertilization by developing an anterior-posterior body axis and consequently divides asymmetrically into two daughter cells with distinct fates22–24. What is the underlying cue that instructs the formation of a polarity axis of an otherwise nonpolarized embryo? Part of the answer lies in the paternally contributed pair of centrioles that enter the oocyte during fertilization. Centrioles mature into centrosomes by recruiting maternally deposited proteins that form the pericentriolar matrix (PCM). It is the centrosomes that finally provide the necessary spatial and temporal cues that break symmetry and leads to the formation of the posterior axis25–28.

Symmetry breaking and polarity establishment in the C. elegans embryo occurs primarily through the centrosome-regulated contractility dependent pathway. A uniformly contracting embryo surface becomes non-contractile in the vicinity of the centrosome at the onset of polarity. The centrosome locally inhibits contractility at the adjacent cortex (presumptive posterior), thereby generating anisotropy in cortical tension that promotes advective cortical flows towards the anterior cell cortex26,29–31 (Figure 1). These anterior-directed cortical flows enable cell polarization by segregating a group of conserved proteins called PAR (Partitioning defective), at the anterior and posterior membrane of the embryo23,24,31,32. In a polarized embryo, anterior PARs [aPARs: PAR-3, PAR-6, and atypical protein kinase C (aPKC)] and posterior PARs [pPAR: PAR-1, PAR-2, and LGL] once localized to anterior and posterior cortical surfaces are maintained in a stable polarized state by reaction-diffusion dynamics33–35. In the absence of actomyosin-dependent cortical flows, polarity set-up is dramatically delayed and relies on a redundant microtubule-based pathway36–38. Importantly, centrosome-cortical distance is critical for regulating the timing of the polarity setup: greater the distance, the longer it takes to break symmetry39. Based on this finding, it was hypothesized that there must a centrosome-localized component/s that is transmitted to the posterior cortex and spatiotemporally controls polarity setup. However, the nature of the protein(s) that guide accurate polarity establishment had remained elusive. Recent work by us and others has shed light on the identity of this signal, revealing that the evolutionarily conserved Aurora A kinase is involved in symmetry breaking, and thus for the accurate polarity setup in the one-cell embryo18–21.

Figure 1. Aurora A kinase orchestrates accurate actomyosin flow.

Figure 1

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(A, B) Cortical view of the actomyosin network in the wild-type embryo (A), and in Aurora A (RNAi) embryo (B). In wild-type embryo, before symmetry breaking (referred to as polarity establishment), the actomyosin cortex (shown as green filaments) is spread over the entire embryo surface. However, centrosome (in red)-induced anterior-directed advective actomyosin flows at polarity establishment phase passively transport cortically associated anterior PAR [aPAR] complex (in magenta), and this leads to loading of the posterior PAR complex [pPARs] (in green) onto the posterior cortex. During late prophase (at the time of pronuclear meeting), there is global disassembly of the actomyosin network that is dependent on cytoplasmic Aurora A (A). Inset of Aurora A kinase gradient at the centrosome in wild-type embryos (A’). Aurora A in its active phosphorylated state, diffuses out to the cortex and locally disassembles the actomyosin cortex at the posterior surface (red arrows indicate the initiation of anterior-directed actomyosin flows), in close vicinity of the centrosome. In Aurora A (RNAi) embryos, the anterior-directed advective actomyosin flow is significantly impaired. The weak clearing of the actomyosin at the extreme anterior and posterior edges results in a bipolar pattern of pPAR polarization, i.e., pPAR loading at the extreme anterior and posterior of the embryo. The actomyosin disassembly during late prophase in these embryos is significantly delayed.

Inset of Aurora A (RNAi) embryos (B), centrosomes do not mature, and spontaneous clearing of the actomyosin cortex occurs at the anterior and posterior, irrespective of the position of the centrosome (B’).

Aurora A is an evolutionary conserved, centrosome-enriched kinase that plays a crucial role in promoting mitotic entry, centrosome maturation, bipolar spindle formation, spindle assembly and cytokinesis40–49. Apart from controlling important mitotic processes, Aurora A regulates polarity establishment in flies and neuronal cells50–54, however, its role in polarity establishment in C. elegans embryos was less appreciated. In this realm, previous work revealed that the loss of Aurora A is associated with abnormal polarity during mitosis; however, whether this was due to its function during polarity establishment was unknown55,56.

Aurora A ensures proper actomyosin contractility and polarity setup

Aurora A depleted embryos exhibit excess contractility at the embryo surface at the time of polarity establishment18. Quantifying the rate of cortical flow revealed that puncta of non-muscle myosin (NMY-2) moved at significantly lower rates in Aurora A (RNAi) embryos compared to control embryos18,20. Since accurate cortical flows are critical for the distribution of the anterior and posterior PAR proteins, loss of Aurora A resulted in a bipolar distribution of PAR-2, in contrast to a single posterior PAR-2 domain in control embryos (Figure 1). While data from various groups indicated that Aurora A (RNAi) embryos form bipolar PAR-2 domains, the proportion of embryos exhibiting this phenotype varied between the reports. Both our lab and Klinkert et al., 2019 found bipolar PAR-2 in the majority of Aurora A (RNAi) embryos, while Zhao et al., 2019 and Reich et al., 2019 reported that the dominant proportion of Aurora A (RNAi) embryos show reverse polarity, i.e., posterior PAR-2 domain forms on the anterior instead. This variability in the bipolar PAR-2 phenotype may arise from differences in RNAi penetrance.

How do Aurora A (RNAi) embryos that lack stereotypical cortical flows polarize PAR-2 in a bipolar fashion? On close examination, it appeared that the minimum clearance of the actomyosin network at the extreme anterior and posterior poles in Aurora A (RNAi) may be sufficient for PAR-2 loading at the anterior and posterior membranes18,20 (Figure 1). In cases of reverse polarity, reported by Zhao et al., 2019, cortical flows are oriented towards the posterior. Despite the differences in the proportion of bipolar PAR-2 domains upon Aurora A depletion among various groups, polarity establishment in these embryos appears to rely on the actomyosin based contractility, since clearing of the actomyosin cortex was found to be a pre-requisite for PAR-2 loading. Because Aurora A depletion affected proper polarity setup, these embryos are also impaired in the correct localization of GFP-PGL-1 and GFP-PIE-1, which demarcate the germline lineage57,58. In control embryos GFP-PGL-1 and GFP-PIE-1 are enriched at the posterior, however in Aurora A depleted embryos these proteins are enriched at the posterior as well as anterior domains18 (Figure 2). Similarly, MEX-5, a polarity mediator protein that is enriched at the anterior in control embryos59, was present in the centre of the embryo in Aurora A (RNAi) background20. These observations altogether establish that Aurora A kinase is critical for proper symmetry breaking and polarity establishment in the one-cell embryo.

Figure 2. Aurora A regulates proper polarity establishment in the one-cell embryo.

Figure 2

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(A, B) In the wild type embryo, before polarity establishment, the entire membrane surface is contractile, and aPARs (in magenta) is localized at the membrane while the pPARs is cytosolic. At the onset of polarity establishment, actomyosin-based cortical flows lead to the removal of the aPAR from the posterior membrane and thereby allowing the pPAR (in green) to occupy that surface. The formation of distinct anterior and posterior PAR domains, and evident asymmetric contractility at the membrane surface, constitutes symmetry breaking and is responsible for polarizing the embryo. As a result germline-specific factor PIE-1 (localized in the cytosol and shown in grey) and PGL-1 (a component of P-granules; shown in green), are relocated and restricted to the posterior of the embryo (A). In Aurora A (RNAi) embryos, the entire membrane surface displays excess contractility, which fails to resolve into a posterior-smooth and anterior-contractile membrane at the time of polarity establishment, as seen in wild-type embryos. Also, Aurora A depleted embryos display a bipolar pattern of pPAR localization at the extreme anterior and posterior poles resulting in PIE-1 and PGL-1 localization to the anterior and posterior region of the embryo (B).

Aurora A regulates polarity independent of its function in microtubule nucleation

The active form of Aurora A is mainly localized to the centrosomes60, and Aurora A activity is critical for preventing excess contractility18–20,49, thus it is proposed that a gradient of active Aurora A emanating from the centrosome breaks symmetry and helps in polarity establishment (Figure 1). However, since Aurora A kinase is important for microtubule nucleation at centrosomes18,19,40,55, and microtubules are also linked with proper polarity establishment61,62, the polarity establishment defect upon Aurora A depletion could simply arise because of its impact on microtubule polymerization function. Notably, γ-tubulin depletion, which equally impacts centrosomal microtubules63,64, did not perturb polarity18. Also, exposing Aurora A depleted embryos to the microtubules poison nocodazole failed to rescue the bipolar PAR-2 domains18,20. Altogether, these observations suggest that the role of Aurora A in establishing a single polarity axis is independent of its role in microtubule nucleation18,20.

Aurora A enrichment to the centrosomal and cortical microtubules is mediated by TPXL-1 (TPX2 in humans)18,19,65–67. Interestingly, embryos lacking TPXL-1 reveal no impact on contractility or on polarity establishment18,19. This data indicates that Aurora A localization at the centrosome-based asters and cortical microtubules is not pivotal for proper polarity set-up. Can cytoplasmic Aurora A similarly ensure global inhibition of contractility? Notably, work from Motegi lab revealed that global disassembly of contractile network during late prophase (a few minutes after polarity establishment) is regulated by cytoplasmic Aurora A, that is independent of its localization at the centrosomes19.

Altogether, data from these studies simply imply that the kinase-active and centrosome-associated Aurora A promotes posterior PAR-2 formation by locally inhibiting the actomyosin network at the time of polarity establishment and the cytoplasmic Aurora A induces global disassembly of actomyosin network later during prophase to ensure the maintenance of PAR polarization (Figure 1).

Centrosomes are dispensable in guiding the polarity axis in the absence of Aurora A

In C. elegans one-cell embryos centrosomes specify the posterior pPAR axis25–28. Since Aurora A is enriched at centrosomes, we and others investigated the relevance of centrosomes in defining the posterior axis in embryos depleted for Aurora A. Notably, in Aurora A (RNAi) embryos that underwent lateral or anterior fertilization, or where the position of the centrosomes was shifted away from the posterior cortex, polarization occurred spontaneously in a bipolar pattern, indicating that in the absence of Aurora A, the location of the centrosome was no longer able to set the polarity axis18,20. This finding was further strengthened by experiments randomizing the position of centrosome in the Aurora A (RNAi) background by co-depleting ZYG-12, a protein required to attach the centrosomes to the nucleus68. Interestingly, in embryos lacking Aurora A and ZYG-12, where the centrosomes are either at the anterior end or appreciably far from either cortex, bipolar polarization occurs spontaneously18. Overall, these findings support the notion that kinase-active AIR-1 enriched on the centrosomes instructs a single axis of posterior PAR-2 polarization.

Aurora A impacts polarity establishment independent of its role in centrosomes maturation

Centrosomes maturation is critical for ensuring robust microtubule polymerization. Aurora A promotes centrosome maturation by recruiting other downstream effectors, such as TBG-1 and ZYG-9. Both of these proteins needed for maintaining precise microtubule length and number at the centrosomes18,40,64,69–71. Thus, the inability of centrosomes to initiate robust asters upon Aurora A loss could be linked with defective centrosome maturation. However, depletion of neither TBG-1 nor ZYG-9 resulted in the bipolar PAR-2 phenotype associated with Aurora A loss18. This indicates that TBG-1 and ZYG-9 are dispensable for proper polarization. Two coiled-coil proteins SPD-2 and SPD-5 (Spindle Defective) act upstream of Aurora A and recruit Aurora A to the centrosome and their loss is linked with polarity defects27,28,62,72 Thus, the polarity establishment defects upon SPD-2 or SPD-5 depletion could be directly associated with either their function in maintaining appropriate pools of Aurora A at the centrosomes or independent of Aurora A. Interestingly, it was also found that that Aurora A also amplifies SPD-5 and SPD-2 signals at the centrosome in a possible feedback loop18,19,28. These results altogether suggest that the triad of SPD-2/SPD-5/Aurora A that forms a regulatory cascade and are co-dependent on each other for efficient centrosome maturation could be involved in polarity establishment. However, in contradiction to this proposal, FRAP analysis has revealed that Aurora A enriched at the centrosomes rapidly exchanges with the cytoplasm, unlike SPD-5 that was found to exhibit a dramatically weak recovery rate19,73,74. From the perspective of the ability to form a diffusible gradient, FRAP results suggest that Aurora A, instead of SPD-5, is more likely to develop an active gradient. To support this hypothesis, Zhao et al., 2019 further show that GFP-Aurora A recruitment to the cortex, but not its kinase-dead form, in spd-5 (RNAi) background, can disassemble the GFP-NMY-2 and is sufficient to polarize the actomyosin network. This line of work strongly suggests that kinase active form of Aurora A diffuses out from the centrosome to the cortex, where its activity alters the properties of the actomyosin network in close vicinity to initiate the actomyosin flows. Local disruption of the actomyosin network results in anterior-directed cortical flows and consequently PARs localization.

RhoA acts downstream of Aurora A in regulating proper polarity

Local exclusion of Rho GEF, ECT-2 at the posterior cortex appears to be essential for creating anisotropy and initiating the actomyosin flow, and concomitant PAR polarity establishment75. Indeed, bipolar PAR-2 axes in Aurora A (RNAi) embryos are dependent on Rho-mediated contractility18. Co-depletion of Aurora A with ECT-2 or its effector protein NOP-1 leads to a single, considerably delayed PAR-2 domain, thereby inhibiting the formation of ectopic anterior PAR-2 domain observed in Aurora A (RNAi) alone18. The single PAR domain seen in Aurora A (RNAi) in the absence of actomyosin contractility could be because of a microtubule-directed pathway that polarizes the embryo even in the absence of Rho activity36,37. Zhao et al., 2019 reached to an analogous conclusion by abolishing contractility using mlc-5 (RNAi) in Aurora A (RNAi) embryos, where they report rescue of their reverse polarity defect, just as we observe a single PAR-2 domain, instead of bipolar PAR-2 axes. Cumulatively, these data suggest that the polarity establishment (bipolar or reverse) that occurs upon Aurora A depletion is dependent on the Rho-mediated contractility. How does Aurora A regulate actomyosin disassembly at the posterior cortex? Recent work showed that Aurora A promotes cytokinesis by clearing contractile ring components from the polar cortex49. Based on our results, which suggest that Aurora A-mediated symmetry breaking is dependent on ECT-2-based contractility, we analyzed the localization of GFP-ECT-2 in Aurora (RNAi) background. Strikingly, we found that upon Aurora A depletion, ECT-2 fails to delocalize from the posterior cortex at the time of polarity establishment in contrast to control embryos (Figure 3)18. This result presumably justifies the excess contractility observed in Aurora A (RNAi) at the time of polarity establishment. Future work is required to find the exact mechanism by which kinase-active Aurora A gradient locally excludes ECT-2 from the posterior cortex and thereby coordinates actomyosin disassembly and establishment of PAR polarity, essential for symmetry breaking. Human Ect2 interacts with the plasma membrane through phosphoinositides76,77. However, whether C. elegans ECT-2 interacts with membrane phosphoinositides is not known. Thus, one tempting possibility is that centrosome Aurora A kinase gradient phosphorylates ECT-2 and changes its affinity towards the membrane in the vicinity of centrosomes. Of course, this assumption must be tested and would require substantial work. The other possibility is that Aurora A phosphorylates component/s acting upstream of ECT-2 in the cortical contractility pathway.

Figure 3. RhoGEF ECT-2 acts downstream of Aurora A kinase in ensuring single polarity axis.

Figure 3

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(A, B) As mentioned in Figure 1, Aurora A loss leads to weak clearing of the actomyosin network from the polar cortical region and bipolar localization of pPARs (A). Co-depletion of ECT-2 and Aurora A significantly delay symmetry breaking, and pPARs does not localize at the cell membrane at the time of polarity set-up; however, it loads on to the membrane only in late prophase, presumably with the help of microtubules-dependent pathway (B; see text).

(C, D) In the wild type embryo, ECT-2 (in violet) is uniformly localized on the entire membrane before polarity establishment. At the polarity establishment phase, ECT-2 is significantly delocalized from the posterior cortex in the vicinity of centrosomes (C). In Aurora A (RNAi) embryos, ECT-2 fails to delocalize from the posterior membrane surface, resulting in uniform contractility at the embryo surface (D).

It is equally important to note that the appearance of two PAR-2 domains upon Aurora A depletion is invariably formed at the anterior and posterior cortical regions. If uniform actomyosin contractility is responsible for improper polarization in Aurora A (RNAi), why are these domains restricted to specific embryo surfaces, i.e., the anterior and posterior poles, only? It could be that the presence of curvature at the anterior-posterior polar surfaces of the embryo might make such domains more amenable for symmetry-breaking. Indeed, using PDMS-based equilateral chambers, Klinkert et al., 2019 revealed that Aurora A depleted embryos, when squeezed into such chambers, form PAR-2 domains at sides that display the highest degree of curvature independent of the position of the centrosomes. This suggests that the curved regions of the embryos are preferentially polarized in Aurora A (RNAi) embryos.

Aurora A suppresses premature activation of PARs in oocytes

Interestingly, Reich et al., 2019 uncovered a novel model of PAR protein activation during oocyte maturation. They observed that PAR-1/PAR-2 [pPARs] predominantly occupy gonad and oocyte membranes before oocyte maturation, such that aPAR proteins, PAR-6 and aPKC-3, cannot localize to the membrane. However, loss of Aurora A leads to premature localization of PAR-6 to the oocyte membranes, indicating that other than its role in regulating polarity establishment in the embryos, Aurora A also controls spatiotemporal localization of PARs in oocytes. This ensures a single polarity axis by the centrosomes during symmetry breaking. The authors further reported that symmetry breaking is accelerated in Aurora A (RNAi) embryos, and they linked this with premature activation of the PAR network, i.e., precocious loading of the aPAR21. However, other groups did report any apparent delay in symmetry breaking in control embryos18–20. This could be because of the difference in relative timing used for assessing the symmetry-breaking event. Nonetheless, data from Reich et al., 2019, reports novel role of Aurora A in ensuring temporal activation of PARs during oocyte maturation, beyond its role in symmetry breaking in the embryo. The differences in the mechanism of action of Aurora A between oocyte maturation and polarity establishment in the embryos, separated over mere minutes in the developmental program of the worm, is an exciting area for future research. Other than the role of Aurora A in ensuring a single polarity axis in the one-cell C. elegans, Drosophila Aurora A is needed for asymmetric cell division in Drosophila neuroblasts. Aurora A directly phosphorylates members of the conserved PAR complex to regulate the asymmetric distribution of fate determinant protein, Numb51. In Drosophila neuroblasts Aurora A-mediated phosphorylation of PAR-6 interferes with its association with aPKC, which is critical for Numb asymmetry78. However, mutation of an evolutionarily conserved residue in C. elegans PAR-6 did not lead to any polarity defect, suggesting that there could be potential differences in regulating polarity among different systems21.

Aurora A is also reportedly amplified in several cancers79. The tumor-suppressive activity of Aurora A could be explained by its role in polarity establishment since the loss of polarity has been linked with tumorigenesis7–16. Since, Aurora A lies at the interface of polarity establishment and tumorigenesis, it would be interesting to test whether the role of Aurora A in symmetry breaking is conserved in mammalian systems and whether its impact on polarity is directly associated with over-proliferation and tumorigenesis. Future work on unravelling the mechanistic details of Aurora A-dependent polarity establishment in C. elegans and other systems will potentially contribute to our understanding of polarity establishment and associated disease.

Perspective.

  • (i)

    highlight the importance of the field

    The proper establishment of cell polarity is critical for life. Errors in this process can lead to developmental defects and cancer.

  • (ii)

    a summary of the current thinking

    Here, we have discussed the recently-identified function of Aurora A kinase in accurate polarity establishment through its action on the actomyosin network.

  • (iii)

    a comment on future directions

    Future investigations should clarify the target of Aurora A and the underlying mechanism by which Aurora A spatiotemporally controls proper polarity setup Since, Aurora A is an evolutionarily conserved kinase, the uncovered mechanism will likely apply to cellular models beyond C. elegans one-cell embryo.

Acknowledgements

We are grateful to Sveta Chakrabarti and Raj Ladher for providing us critical comments on this manuscript. This work is supported by the Department of Biotechnology (DBT)-Indian Institute of Science Partnership Program and by grants from the Wellcome Trust/DBT India Alliance Fellowship (IA/I/15/2/502077 to S. Kotak). S. Kotak is a Wellcome Trust DBT-India Alliance Intermediate Fellow.

Footnotes

Authors contributions

S. Kapoor and S. Kotak wrote the manuscript, and Funding was acquired by S. Kotak.

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