Sugioka, K. | Search bioRxiv

bioRxiv2017

Cell-nonautonomously tunable actomyosin flowsorient distinct cell division axes

Cell division axes during animal development are arranged in diverse orientations, but the molecular mechanisms underlying this diversity remain unclear. By focusing on oriented divisions that are independent of known microtubule/dynein pathways, we show here that the non-muscle myosin II motor is an extrinsically tunable force generator that orients cell division axes through cortical actomyosin flows. We identified three extracellular cues that generate different actomyosin flows. A single contact site locally inhibited myosin activity in a mechanosensitive manner to generate local flow asymmetry, while size asymmetry of two contact sites and Wnt signaling both polarized myosin activity and actomyosin flow, with the latter overriding mechanosensitive effects. These intracellular actomyosin flow anisotropies specify distinct division axes to establish the geometries of not only Caenorhabditis elegans 4-, 6-, and 7-cell stage but also mouse 4-cell stage embryos. Tunable actomyosin flows together with microtubule/dynein pathways may specify diverse division axes across species.

cell biology↗

bioRxiv2017

The tumor suppressor APC is an attenuator of spindle-pulling forces during C. elegans asymmetric cell division

The adenomatous polyposis coli (APC) tumor suppressor has dual functions in Wnt/{beta}-catenin signaling and accurate chromosome segregation, and is frequently mutated in colorectal cancers. Although APC contributes to proper cell division, the underlying mechanisms remain poorly understood. Here we show that C. elegans APR-1/APC is an attenuator of the pulling forces acting on the mitotic spindle. During asymmetric cell division of the C. elegans zygote, a LIN-5/NuMA protein complex localizes dynein to the cell cortex to generate pulling forces on astral microtubules that position the mitotic spindle. We found that APR-1 localizes to the anterior cell cortex in a Par-aPKC polarity-dependent manner and suppresses anterior centrosome movements. Our combined cell biological and mathematical analyses support the conclusion that cortical APR-1 reduces force generation by stabilizing microtubule plus ends at the cell cortex. Furthermore, APR-1 functions in coordination with LIN-5 phosphorylation to attenuate spindle pulling forces. Our results document a physical basis for spindle-pulling force attenuation, which may be generally used in asymmetric cell division, and when disrupted potentially contributes to division defects in cancer.\n\nSignificance StatementAPC (adenomatous polyposis coli) is a Wnt signaling component as well as a microtubule-associated protein, and its mutations are frequently associated with colorectal cancers in humans. Although APC stabilizes microtubules (MTs), its mechanical role during cell division is largely unknown. Here we show that APC is an attenuator of forces acting on the mitotic spindle during asymmetric cell division of the C. elegans zygote. We performed live-imaging, laser-microsurgery, and numerical simulation to show how APC suppresses spindle pulling force generation by stabilizing microtubule plus-ends and reducing microtubule catastrophe frequency at the cell cortex. Our study is the first to document a mechanical role for the APC protein, and provides a physical basis for spindle-pulling force attenuation.

cell biology↗