CAREER: Protein degradation during the maternal-to-zygotic transition

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For all life forms, development is a highly synchronized and fundamental process. The initial stages of animal development are directed by biomolecules that were made by the mother and deposited into the growing egg. Once they have served their role, these maternal biomolecules must be removed and replaced with new ones made by the embryo. This process, known as the maternal-to-zygotic transition, is essential for animal embryogenesis. Despite the importance of the maternal-to-zygotic transition, little attention has been placed on understanding how maternal proteins are removed. The goal of this CAREER award is to fill this gap through a combination of genetic and molecular biology techniques. This research will provide an entry point into three poorly understood, but critical, questions: 1) how do embryos target maternal proteins for degradation; 2) how is protein degradation controlled during development; and 3) what are the developmental consequences when this process goes awry? This award will also provide 15-month paid internships to undergraduates who identify as underrepresented minorities and study at a local undergraduate institution, Metropolitan State University of Denver (Metro). Meaningful research experiences, like the ones provided by this award, will set the students on a trajectory of success in science. This award will thus map the enormous scope of protein removal in driving embryogenesis, will transform the educational ecosystem in Denver, and ultimately will help to increase diversity in science. In Drosophila melanogaster, an E2 ubiquitin-conjugating enzyme known as “Marie Kondo” removes several maternal proteins that were critical for oogenesis but are not needed by the embryo. Marie Kondo works with an E3 ubiquitin ligase called the CTLH complex. However, little is known about how Marie Kondo and the CTLH complex are controlled. Using a combination of genetics and molecular biology, this project will investigate the mechanisms underlying the tight temporal control of substrate specificities and enzymatic activities of Marie Kondo and its partner, the CTLH complex, and determine the developmental consequences of mistiming their activity. Finally, as part of the educational program, an RNAi-based screen will be used to identify other E2s and E3s essential for the Drosophila embryogenesis, which will set the stage for future investigations in maternal protein removal during the maternal-to-zygotic transition. Together, these investigations will shed light on a new area of developmental biology—protein decay—that is critical for the creation of an adult animal from a single-cell embryo.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.