Cells often send messages to each other in the form of proteins secreted from one cell and received at the surface of a neighboring cell. One important family of signaling proteins is called the "Wnt" family. Wnt family proteins are essential for embryonic cells and adult stem cells to polarize, i.e., to position specific cellular components on one side of a cell. Wnt signaling also plays critical roles in cancer, and loss of cell polarity is an early hallmark of many cancers. As a result, there is great interest in understanding exactly how Wnt signals work to polarize cells. Whether Wnt signals function as positional cues for cell polarization, or alternatively as permissive signals that function with unknown positional cues, has long been a matter of debate. This project uses an innovative system in which one can position a Wnt signaling source on a single cell and follow cell polarization in living cells by filming the movements of fluorescently-tagged proteins through a microscope. Preliminary results using this system have produced a surprise: Although Wnt-expressing cells can function as positional cues for cell polarization, purified, active Wnt protein cannot. This result raises the possibility that Wnt proteins may be permissive signals for cell polarization directed by as-yet unknown cues. This hypothesis will be examined to reveal the exact mechanisms of cell polarization, and by identifying important molecules involved in these mechanisms. This project will also train students to conduct research.
This project as resulted in important scientific findings, and it has resulted in broader impacts including training people in scientific research. (1) Scientific findings: We developed improved methods for genome engineering that have been adopted by much of the C. elegans research community, engineering the C. elegans genome using Cas9-triggered homologous recombination. This method is likely to impact diverse areas of biological sciences, as the model organism C. elegans is used to investigate mechanisms in diverse fields including developmental biology, cell biology, and neurobiology. We have also discovered specific mechanisms by which a proto-oncogene (a normal gene that contributes to cancer when mutated) functions in cell division orientation mechanisms in response to cell-cell signaling. Our findings inform emerging ideas about possible contributions of cell division misorientation to early steps of certain cancers. And our recent work on a gene of interest, identified during the course of this work, can inform why lesions in a homologous gene in mammals can result in neural tube defects—suggesting that multiple genes' transcription may be misregulated when the gene of interest is malfunctioning. (2) Broader impacts: graduate students, postdoctoral fellows, and undergraduate students were trained in scientific research. Two of the postdoctoral fellows are now Assistant Professors at US universities. Trainees included members of populations traditionally underrepresented in scientific careers including a minority trainee and trainees with physical disabilities. Work was disseminated through scientific publications, a temporary museum exhibit, and science outreach videos.
