NSF/BIO-UKRI/BBSRC: Synthetic induction of self-organized cell patterning and morphogenesis

Cell division is a fundamentally important process and when cell division goes awry, pathologies such as cancers, impaired healing, infertility, and abnormal development occur. This project focuses on crucial cell division events at the outer part of the cell called the cell cortex. Synthetic proteins and artificial intelligence will be used to better understand these cell division events, what goes wrong in certain pathological states, and how to artificially promote cell division when it is compromised. In addition to these research outcomes, this work will help prepare our future scientific workforce by training high school and college students in synthetic biology, molecular biology, and AI assisted protein design. The cell cortex is the primary driver of cell shape changes. Such shape changes often arise due to Rho GTPases, which self-organize into cortical patterns that direct formation of corresponding patterns of the contractile machinery--actin filaments and myosin-2 (actomyosin). A prototypical example of such self-organization is provided by cytokinesis, during which Rho waves direct the formation of actomyosin waves at the equatorial cortex, thereby driving furrowing. Ect2, a Rho activator, and RGA-3/4, a Rho inactivator, drive Rho wave formation via coupled positive and negative feedback. Normally, Rho waves are focused and amplified at the equatorial cortex by the mitotic spindle, thereby driving furrowing and, ultimately, cytokinesis. However, synthetic proteins designed to mimic Ect2 and RGA-3/4 can induce formation of actomyosin waves in nondividing cells and, remarkably, these synthetic waves spontaneously self-organize into patterns that drive cell furrowing and other shape changes. In this work, the features of the synthetic proteins that lead to self-organization of the cortical contractile waves will be determined, as will the features of Ect2 and RGA-3/4 that prevent such self-organization. Thus, this work will reveal both general and specific molecular connections between self-organized cortical patterns and the regulatory proteins that generate such patterns. This collaborative US/UK project is supported by the US National Science Foundation (NSF) and the UK Biotechnology and Biological Sciences Research Council (BBSRC), where NSF funds the US investigator and BBSRC funds the partners in the UK. 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.