Proper control of cell polarity is essential for all cells. Healthy mammalian epithelial cells maintain apical basal polarity, while cancerous epithelial cells exhibit defects in the orientation of their division axis, and loss of polarity. Our studies using the nematode C. elegans combine genetic, molecular, biochemical and live imaging approaches to investigate how specific proteins are used to regulate polarized movements at key points in development. We used genetics to uncover a pathway that links signals at the plasma membrane to the recruitment of the WAVE complex, a powerful regulator of Arp2/3, the only known nucleator of polarized branched F-actin. Our studies have shown that the force of polarized branched actin can move vesicles, can position the nucleus, and generates the membrane protrusions that permit cell and tissue migrations. Current projects include mechanistic studies to understand how branched F-actin helps to initiate and maintain cell polarity during cell migrations and cell homeostasis, and how polarity signals between tissues are used to polarize the cytoskeleton. We have also discovered and are investigating novel regulators of morphogenesis. This work has implications for human health, from different cancers, in which the regulators of branched actin are often mutated, to neuronal development, where mutations in branched actin regulators are associated with autism and schizophrenia.
Figure 1. Branched F-actin contributes to nuclear positioning, tissue movements, and epithelial polarization. Our lab has investigated all of these developmental roles of branched actin.
Figure 2. A pathway connects signals at the plasma membrane to the recruitment of the WAVE Complex, which results in polarized nucleation of branched actin. The force created by branched actin can push the membrane to permit cell migrations, and promotes apical/basal polarity through a mechanism that is still not well understood.
Figure 3. The function and localization of branched actin regulators.
Left panels show the dramatic changes in cell shape and F-actin distribution when arp-2, a regulator of branched actin, is depleted from embryos during morphogenesis. The arp-2 depleted embryo will die because epidermal cell migrations will completely fail.
The transgene illustrates F-actin enrichment specifically in the epidermis.
Right panels: Endogenous WVE-1 protein is enriched in the developing nerve ring (thin arrow), a structure that organizes the CNS, and in the apical intestine, a polarized epithelium.