Mechanisms of Guidance Cue Regulation During Single and Collective Cell Migration

Directed cell migration is critical for embryonic development, homeostasis and disease. Many migrating cells rely on gradients of secreted guidance cues for the information that helps them navigate complex and dynamic environments with spatio-temporal precision and accuracy. While gradient formation via diffusion of a guidance cue from a point source is plausible for simple, static systems, it is becoming increasingly clear that regulatory mechanisms are often required to generate and maintain biologically useful directional cues. Although initially discovered for their role in the immune system, chemokines, or chemotactic cytokines, have been implicated in many cell migration events that are critical to animal development. While these events are numerous, the chemokines known to guide them are few, suggesting an economy of scale that likely increases efficiency within the developing embryo. For example, the chemokine SDF1/CXCL12, which is the focus of my dissertation, simultaneously guides various cells to different targets. This increased efficiency and elegance, however, comes at a cost: augmented risk of infidelity due to cells responding to inappropriate sources of a commonly used cue. I address this issue in chapter one, which describes a novel mechanism of guidance cue regulation that helps a disparately born set of neurons in the developing zebrafish embryo reach a common assembly site while avoiding potential distractions. In chapter two, I address another challenge encountered during embryonic cell migration. While some cells such as the neurons discussed in chapter one have a relatively short journey, others face considerably longer migration routes. The cells of the zebrafish posterior lateral line primordium, for example, must travel a distance of ∼1.2 millimeters, or ∼150 times the length of a single cell, over a 20-hour period. It is difficult to imagine that the classic point source diffusion model of gradient formation is tenable for such scenarios. Using a novel, quantitative biosensor in live zebrafish, my colleagues and I reveal a near-steady state, linear chemokine signaling gradient that is autonomously generated and maintained by a migrating cell collective. This in vivo evidence supports the classic source-sink diffusion model of gradient formation proposed by Francis Crick in 1970.