CAREER: Contact inhibition of locomotion as a positioning mechanism during endoderm morphogenesis

University Of California - Merced, Merced CA

Investigators

Abstract

In multicellular organisms, tissues, organs, and even the entire body plan are built through the actions of many individual cells. Understanding how cells coordinate their actions with each other remains an outstanding question in biology. This study will use zebrafish embryos to understand how a population of embryonic cells called endodermal cells work together to build a tissue that will eventually become parts of the gastrointestinal and respiratory systems. In humans, endoderm malformations affect an estimated 10 per 10,000 births. Zebrafish embryos will be used in this study because they are transparent and develop externally (outside the mother), making it easy to image cellular interactions within a living, intact organism. Preliminary work suggested that, counterintuitively, zebrafish endodermal cells disperse apart before coming back together to form a tissue. This study aims to understand how and why endodermal cells undergo these two very different behaviors (dispersal and convergence) during tissue formation. This research will be integrated with an education and outreach program designed to expand access to authentic research experiences and enhance STEM education for undergraduate students and the general public. This education and outreach program consists of: 1) a course-based undergraduate research experience (CURE) for students enrolled at the University of California, Merced, 2) a summer program that will give undergraduate students direct experience working on an independent project in a research lab, and 3) an educational exhibit on developmental biology and microscopy for a local children’s’ museum designed in partnership with teachers-in-training. The endoderm is one of the three primary germ layers that gives rise to the gut and respiratory epithelia and other organs. However, endodermal cells are highly migratory during gastrulation and before differentiating into mature epithelia. This study will take advantage of the zebrafish embryo’s amenability for in vivo imaging to characterize the continuum of cellular behaviors that occur as cells differentiate from migratory endodermal precursors into epithelial cells. During gastrulation stages, zebrafish endodermal cells first disperse away from each other before eventually converging into a coherent epithelial sheet. Preliminary studies suggested that endodermal cells initially avoid each other through contact-triggered inhibition of locomotion. This study will determine the molecular mechanisms driving these inhibitory interactions and their significance to tissue formation. Aim 1 will identify the cell surface receptors that allow endodermal cells to recognize and repel away from each other. Aim 2 will define the intracellular signaling pathways that regulate inhibitory responses and the initial dispersal of endodermal cells. Aim 3 will determine how these inhibitory interactions are modulated as cells switch from dispersal to convergence movements. This study will demonstrate how transient, hyperlocal cell-cell interactions can lead to large-scale patterning, with broad implications for tissue morphogenesis. 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.