Defects in both cytokinesis and cell polarity are associated with human disease such as cancer but the possible causal link between them remains unknown. Cytokinesis is the physical division of one cell into two, accomplished by the construction of a contractile ring composed of filamentous actin and the motor myosin-II. When the two daughter cells receive the same cytoplasmic and cortical components and inherit the same cell fate, the division is referred to as symmetric. However, in many specialized cell divisions, such as during embryogenesis and in stem cells, division is asymmetric, resulting in daughter cells with different cell fates and/or of different sizes. In animal cells, asymmetric division is controlled by the PAR proteins (PARtitioning defective), which localize to the cell cortex and ensure each daughter cell receives the proper cell fate determinants. The PAR proteins are thought to regulate asymmetric cell division indirectly by dictating the position and orientation of the mitotic spindle, which then positions the actomyosin contractile ring to drive cell division. However, our preliminary data suggests that the PAR proteins also promote cytokinesis directly by increasing the robustness of contractile ring assembly and constriction. In the C. elegans zygote, the PAR proteins localize to distinct anterior (aPARs) and posterior (pPARs) cortical and cytoplasmic domains to establish the anterior-posterior axis. We found that loss of either the cortical aPARs or pPARs enhanced the cytokinesis failure rate in mutants with weakened contractile rings. Further, we found that the PAR proteins promote the recruitment of filamentous actin and myosin-II to the contractile ring. Based on these data, our central hypothesis is that the PAR proteins protect against cytokinesis failure by contributing to the robustness of contractile ring constriction. In this proposal, we will determine the molecular mechanisms that mediate this protection against cytokinesis failure in three ways: 1) We will identify the specific molecular components of the polarity machinery (PAR proteins and PAR interacting proteins) that are required for cytokinesis protection; 2) we will determine the cellulr mechanism(s) of protection from cytokinesis failure by the PAR proteins; and 3) we will determine if PAR proteins play a more general role in protecting cytokinesis during embryogenesis in a multicellular context. As both cytokinesis failure and dysregulation of cell polarity are regulated by evolutionarily conserved molecular mechanisms and both are emerging as biomarkers for human diseases such as cancer, our work will have relevance for human health.
An emerging feature of differential cell fate specification is the differential regulation of basic cell biological processes. As an example of this, we found that th proteins that regulate cell polarity in asymmetrically dividing cells also regulate cytokinesis, th physical division of one cell into two. PAR proteins (PARtionioning defective) protect polarized cells from cytokinesis failure when the contractile ring is weakened in C. elegans embryo, a genetically tractable model organism. This project investigates the molecular mechanisms underlying PAR protein-mediated protection of cytokinesis, with the long-term goal of identifying molecular targets to improve treatment of human diseases that involve defects in both cytokinesis and cell polarity signaling, such as cancer.
|Ulgherait, Matt; Chen, Anna; Oliva, Miles K et al. (2016) Dietary Restriction Extends the Lifespan of Circadian Mutants tim and per. Cell Metab 24:763-764|