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Developmental Biology - Cell Structure

Asymmetry Cues Cell Function Via Structure

Breaking cell symmetry allows zygote to begin...

Even before the fertilised egg or zygote can start dividing into daughter cells to form tissues and organs, it needs to become asymmetric, or polarised, in shape and molecular organisation. The master switch triggering this symmetry break up in Caenorhabditis elegans (C. elegans) zygotes, was recently identified in a study led by Assistant Professor Fumio Motegi, Principal Investigator at the Mechanobiology Institute (MBI), National University of Singapore (NUS).

The work is published in Developmental Cell in March 2019.
Contrary to the perception of cells as perfect spheres, commonly depicted in school textbooks, cells in our body assume asymmetric or skewed physical shapes. This asymmetry acts as an important spatial cue for many fundamental cell processes, such as cell division, and which direction to move in to proceed normally. Aurora-A kinase is the symmetry breaking cue in the zygote of the nematode worm, C. elegans.

A wealth of information is now available on structure and molecular change taking place as a cell assumes an asymmetric or polarised state. Structurally, cells acquire top, bottom, front and rear surfaces at the molecular level. Special protein groups called polarity regulators move to distinct regions in the cell cortex (a layer beneath the cell membrane), resulting in cell regions acquiring specific architectural functions.
However, relatively little is known about the 'master switch' initiating spatial segregation of cellular components a process known as symmetry breaking. An unanswered central question is the cue guiding polarity regulators towards their destined locations. Motegi set out to unravel the identity of this master switch.

By studying the process of symmetry breaking in zygotes of the nematode worm Caenorhabditis elegans, Motegi's team previously revealed how forces generated on the cortex by the contractions of the actin cytoskeleton (a filament network madeup of actin and myosin proteins) directed movement of polarity regulators to their destined locations. Shortly after fertilisation, actomyosin contractions in the cell cortex puts the surface of the zygote under tension. Upon symmetry breaking, inhibition of actomyosin contractions leads to imbalance on surface tension, allowing cortical cytoskeletal networks to flow and transport polarity regulators.

In the current study, Motegi and his NUS doctoral student Peng Zhao, ventured to identify cues that break symmetry in cortical actomyosin contractions and initiate polarity in C. elegans zygotes. Using a technique called RNA interference to block synthesis of specific proteins involved in the polarisation process, they observed a protein called Aurora-A (AIR-1 in C. elegans) act as the master switch for symmetry breaking.
Aurora-A is a kinase or protein that regulates activity in other proteins by adding a phosphate molecule is well-known for controlling cell division by assembling centrosomes to organize microtubule filaments during cell-cycle division.

They identified a two-stage process by which Aurora-A influences actomyosin contractions. In the first stage, Aurora-A accumulates around centrosomes and suppresses actomyosin contractions locally in the cell cortex. This creates force differences in regions of the cortex, the resulting cortical flow transports myosins and other polarity proteins to the front of the zygote, thereby creating front-rear asymmetry. In the second stage, Aurora-A diffuses into the cytoplasm and suppresses actomyosin contractions across the entire cortex. This prevents further cortex flow or movement of polarity regulators, effectively locking them in place.
"This study provides a key piece to the puzzle of how cell polarity is triggered and established. The single master switch, Aurora-A, creates 'polar lights' that cover one of the cell poles for symmetry breaking."

Fumio Motegi PhD, Temasek Life-Sciences Laboratory, Singapore; Assistant Professor, Department of Biological Sciences, National University of Singapore; Mechanobiology Institute, National University of Singapore, Republic of Singapore.

Intriguingly, the research team discovered the role of Aurora-A in cell polarisation was independent of its role in centrosome assembly and cell-cycle progression. Through fruitful collaborations with colleagues at NUS, including Associate Professor Yusuke Toyama (MBI) and Professor Thorsten Wohland (NUS Department of Biological Sciences), who brought their expertise in laser ablation and fluorescence correlation spectroscopy respectively, demonstrated that the local accumulation of Aurora-A was sufficient to induce symmetry breaking via its kinase activity, regardless of the involvement of centrosomes.

Recent studies in the field have linked abnormal Aurora-A kinase activity with cancerous cell transformations. Researchers hope findings from their study sheds light on this pathogenic association. Although there are still missing links remaining before whole cell polarization is understood, identifying Aurora-A as the master switch controlling cell polarization is crucial to uncovering further details about this essential biological process.
Growing evidence suggests polarisation acts as a key checkpoint for preventing tumorigenic events in cells. Dysregulation in this process can ultimately lead to the onset of carcinogenesis. This study sets the stage for novel therapies for cancers based on manipulating and restoring cell polarity.

Aurora-A around centrosomes locally interferes cortical actomyosin contractility
Aurora-A later mediates global actomyosin disassembly to facilitate symmetry breaking
Translocation of Aurora-A to the cortex is sufficient to trigger symmetry breaking
Aurora-A induces symmetry breaking independently of its roles in centrosome maturation

Cell polarity is facilitated by a rearrangement of the actin cytoskeleton at the cell cortex. The program triggering the asymmetric remodeling of contractile actomyosin networks remains poorly understood. Here, we show that polarization of Caenorhabditis elegans zygotes is established through sequential downregulation of cortical actomyosin networks by the mitotic kinase, Aurora-A. Aurora-A accumulates around centrosomes to locally disrupt the actomyosin contractile activity at the proximal cortex, thereby promoting cortical flows during symmetry breaking. Aurora-A later mediates global disassembly of cortical actomyosin networks, which facilitates the initial polarization through suppression of centrosome-independent cortical flows. Translocation of Aurora-A from the cytoplasm to the cortex is sufficient to interfere with the cortical actomyosin networks independently of its roles in centrosome maturation and cell-cycle progression. We propose that Aurora-A activity serves as a centrosome-mediated cue that breaks symmetry in actomyosin contractile activity, and facilitates the initial polarization through global suppression of cortical actomyosin networks.

Peng Zhao, Xiang Teng, Sarala Neomi Tantirimudalige, Masatoshi Nishikawa, Thorsten Wohland, Yusuke Toyama and Fumio Motegi.

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May 21 2019   Fetal Timeline   Maternal Timeline   News  

C. elegans zygote in the process of symmetry breaking. Spatial uniformity in cortical myosin-II (BLUE) is lost to establish anterior-posterior polarity (clockwise order from the top). Local and global downregulation is controlled by the mitotic kinase, Aurora-A (ORANGE).
Credit: Mechanobiology Institute, National University of Singapore.

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