Quantifying and perturbing the movement of extracellular signaling proteins

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Extracellular signaling molecules coordinate early embryonic development. In zebrafish, the secreted Nodal signaling proteins were proposed to function as classical morphogens that disperse from a localized source to control the development of distant cells. However, recent findings suggest that Nodals may not move over a distance and instead signal mainly to neighboring cells which, due to Nodal auto-induction, relay the signal to distant cells. I will present experiments performed in zebrafish embryos in which I directly test these two models of Nodal signaling and my efforts to unveil the mechanisms of Nodal dispersal.

First, I assessed the endogenous Nodal signaling range in transplantation experiments and tested whether Nodal dispersal requires a relay mechanism. Second, I established that the diffusion of extracellular proteins can be tuned with membrane tethers. Using these tethers as tools, I found that the high diffusivity of Leftys long-range Nodal inhibitors is important to robustly dampen Nodal signaling. Third, I wanted to reveal the molecular basis for the vastly different diffusivities of the long-range Leftys and the short-range Nodals. I will present my findings of co-immunoprecipitation/mass spectrometry experiments to identify putative Nodal diffusion regulators that may explain the short Nodal range. Together, my data support a model in which zebrafish Nodals disperse in the tissue to signal over short distances which is consistent with the idea that Nodal diffusion underlies embryonic tissue patterning.

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