Modeling of Wnt-mediated tissue patterning in vertebrate embryogenesis

Abstract

During embryogenesis, morphogens form a concentration gradient in responsive tissue, which is then translated into a spatial cellular pattern. The mechanisms by which morphogens spread through a tissue to establish such a morphogenetic field remain elusive. Here, we investigate by mutually complementary simulations and in vivo experiments how Wnt morphogen transport by cytonemes differs from typically assumed diffusion-based transport for patterning of highly dynamic tissue such as the neural plate in zebrafish. Stochasticity strongly influences fate acquisition at the single cell level and results in fluctuating boundaries between pattern regions. Stable patterning can be achieved by sorting through concentration dependent cell migration and apoptosis, independent of the morphogen transport mechanism. We show that Wnt transport by cytonemes achieves distinct Wnt thresholds for the brain primordia earlier compared with diffusion-based transport. We conclude that a cytoneme-mediated morphogen transport together with directed cell sorting is a potentially favored mechanism to establish morphogen gradients in rapidly expanding developmental systems. How entire organisms develop out of single cells is a long-term challenge in the life sciences. Morphogens are crucial signaling molecules organizing cell fates and patterning by their local concentrations. While many morphogens diffuse freely, specialized cell extrusions can facilitate directed cell-to-cell transport for morphogens of the Wnt/β-Catenin family. We performed simulations of quickly growing tissue take this into account, back to back with in-vivo experiments. Our simulations suggest that stochasticity effects lead to non-physiological fluctuating boundaries of tissue regions if not properly controlled. Such control can be achieved via directed cell sorting and apoptosis. We provide experimental evidence for both mechanisms. We observe a distinct temporal difference between the transport mechanisms, with cytonemes facilitating an earlier establishment of a stable pre-pattern. Overall, simulations suggest that cytoneme-mediated Wnt transport is advantageous over diffusion-based transport and a potential general mechanism to establish morphogen gradients in rapidly expanding developmental systems.