Dissecting the Mechanism and Function of Cortical Flow During Symmetry-Breaking of Cell Division
Cell divisions in developing animals are not always symmetric (Fig. A) but often exhibit asymmetric patterns during organogenesis and stem cell division, employing cytoskeletal networks and molecular motors (Fig. B-D). Defects in symmetry-breaking of cell division are linked with cancer and congenital disease such as microcephaly. Emerging evidence suggests that a collective directional movement of the cell cortex at the cell surface, known as cortical flow, has the potential to regulate diverse symmetry-breaking events during cell division. However, it remains unclear how cortical flow regulates these processes. Cortical flow is manipulable. For example, we have identified three contact-dependent cues—physical contact, asymmetry in contacting cell sizes, and Wnt signaling—that generate distinct cortical flow patterns and specify different division axes in early embryos. Our goal is to elucidate the molecular and physical mechanisms underlying multimodal regulation of cortical flow and to determine how these dynamics influence the cytokinetic contractile ring and cellular patterning.(Ref: Sugioka and Bowerman., Developmental Cell 2018; Sugioka., Seminars in Cell and Developmental Biology 2022).
Project 1: Elucidating the role of cortical flow in unilateral cytokinesis
Unilateral cytokinesis is characterized by asymmetric closure of the contractile ring and is commonly observed in animal zygotes and epithelia, including those in humans. Aberrant unilateral cytokinesis leads to defects in kidney tubule formation and epithelial polarity. We developed an integrative 4D image analysis pipeline to study unilateral cytokinesis in early C. elegans embryos and found that contractile ring closure is asymmetrically regulated through mechanical control of cortical flow. We have identified a potential molecular mechanism underlying the mechanosensory process of the contractile ring and are now poised to dissect the underlying mechanisms in greater detail.
Ref: Hsu, Sangha et al., Nature Communications (2023)
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Unilateral cytokinesis in zygotes. The myosin II motor protein is fluorescently labeled.
Project 2: Elucidating the role of cortical flow in regulating animal left-right asymmetry
Animal left–right asymmetry is critical for physiological function. For example, the asymmetric positioning and structure of our organs are indispensable for proper function, and congenital conditions known as laterality defects often require lifelong care. However, only about 15% of known genes—primarily those related to cilia and Nodal signaling—can explain the causes of these defects.
Interestingly, actomyosin components are more broadly involved in the generation of left–right asymmetry across diverse organisms, suggesting an evolutionarily ancient mechanism. By taking advantage of C. elegans, which lacks motile cilia, we will uncover how actomyosin regulates left–right asymmetry. In a recent study, we discovered that the major cell adhesion molecule cadherin undergoes left–right asymmetric cortical flow (“chiral cadherin flow”), which is linked to rightward asymmetric contractile ring closure, the first morphological left–right asymmetry observed in C. elegans.
Ref: Khor et al., Current Biology (2025)
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Cadherin dynamics (green) during the second mitosis. The left–right asymmetric cadherin pattern is associated with rightward contractile ring closure. Magenta: plasma membrane.
Project 3: Elucidating the role of cortical flow in asymmetric cell division
Asymmetric cell division is a process by which a mother cell produces two distinct daughter cells. It is one of the major mechanisms for generating cellular diversity during animal development. Defects in regulators of asymmetric cell division are associated with cancer and congenital diseases such as microcephaly. Recent studies also show that cancer stem cells acquire resistance to drug treatment through dysregulated asymmetric cell division. We will investigate the mechanism and function of cortical flow during asymmetric cell division.
Wnt-dependent asymmetric cell division of the endomesodermal precursor cell gives rise to anterior mesoderm and posterior endoderm. Wnt-signaling pathway components localize asymmetrically during this process. Cortical flow is also polarized.
We are using quantitative imaging and genetics to approach these questions.
