Modeling the self-organized phosphatidylinositol lipids signaling system in chemotactic cells based on quantitative image analysis

Advance Online Publication August 16, 2012 doi: 10.1242/?jcs.108373 The phosphatidylinositol (PtdIns) lipids reaction is a key signaling event; this signal is responsible for gradient sensing in eukaryotic cell chemotaxis. The self-organization activity of the PtdIns lipids reaction induces an inherent polarity even in the absence of an external chemoattractant gradient by producing a localized PtdIns 3,4,5-trisphosphate [PtdIns(3,4,5)P3]-enriched domain on the membrane. Experimentally, we found that such a domain could exhibit two types of behavior: 1) persistent domain formation that travels on the membrane and 2) stochastic formation of transient domains. Taking advantage of the simultaneous visualization of PtdIns(3,4,5)P3 and its enzyme, phosphatase and a tensin homolog (PTEN), the inter-dependence of their spatiotemporal dynamics was demonstrated statistically. Based on this statistical analysis, we developed a theoretical model for the self-organization of PtdIns lipids signaling that can accurately reproduce both persistent and transient domain formation; these types of formations can be explained by the oscillatory and excitability properties of the system, respectively.

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Wnt5a signaling controls cytokinesis by positioning ESCRT-III to the proper site at the midbody

Advance Online Publication July 23, 2012 doi: 10.1242/?jcs.108142 Wnts activate at least two signaling pathways, the ß-catenin-dependent and -independent pathways. Although the ß-catenin-dependent pathway is known to contribute to G1/S transition, involvement of the ß-catenin-independent pathway in cell cycle regulation remains unclear. Here, we show that Wnt5a signaling, which activates the ß-catenin-independent pathway, is required for cytokinesis. Dishevelled 2 (Dvl2), a mediator of Wnt signaling pathways, was localized to the midbody during cytokinesis. Beside the localization of Dvl2, Fz2, a Wnt receptor, was detected in the midbody with an endosomal sorting complex required for transport III (ESCRT-III) subunit, CHMP4B. Depletion of Wnt5a, its receptors, and Dvl increased multinucleated cells. The phenotype observed in Wnt5a-depleted cells was rescued by the addition of purified Wnt5a but not that of Wnt3a, which is a ligand for the ß-catenin-dependent pathway. Moreover, depletion of Wnt5a signaling caused loss of stabilized microtubules and mislocalization of CHMP4B in the midbody, which affected abscission. Inhibition of the stabilization of microtubules at the midbody lead to the mislocalization of CHMP4B, while depletion of CHMP4B did not affect the stabilization of microtubules, suggesting that the correct localization of CHMP4B depends on microtubules. Fz2 was localized to the midbody in a Rab11-dependent manner probably along stabilized microtubules. Fz2 formed a complex with CHMP4B upon Wnt5a stimulation and was required for proper localization of CHMP4B at the midbody, while CHMP4B was not necessary for the localization of Fz2. These results suggest that Wnt5a signaling positions ESCRT-III in the midbody properly for abscission by stabilizing midbody microtubules.

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