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Spatiotemporal Manipulation of Hindbrain Development and Cancer Induction in Live Zebrafish via Optical Tools

  • Author(s): Feng, Zhiping;
  • Advisor(s): Weiss, Shimon;
  • et al.

Living organisms are made of cells that are capable of responding to external signals by modifying their internal state and subsequently their extracellular context. Understanding the spatio-temporal dynamics of these complex interaction networks in biological systems is the subject of a field known as systems biology. To investigate these interactions (a necessary step before understanding or modeling them), one needs to develop means to control or interfere spatially and temporally with these processes and to monitor their responses on a fast timescale and with single-cell resolution. Among all the great tools to precisely perturb the dynamics of biological networks, light activation has been witnessed as an extremely powerful, non-invasive methodology, providing an accurate control over biomolecules’ activity at an unprecedented resolution. This dissertation exemplifies the advantages of using optical tools to investigate complex bioprocesses with studies in two different fields which are developmental biology and cancer biology. In the first project, we show how photo-isomerization of the 13-cis retinoic acid to the trans-isomer (and vice versa) could be used in studying retinoic acid’s role in hindbrain development during zebrafish embryogenesis. The second project employs photon uncaging to induce oncogenic expression, and models tumor evolution from single cells in the zebrafish. Developing and validating these tools in these two projects greatly facilities our understanding of several biological networks. Photo-isomerization of retinoic acid between all-trans and cis form helps illuminate retinoic acid’s unique spatial distribution and function on hindbrain development in a developing zebrafish embryo. And this again clarifies the long-standing controversy of retinoic acid acting as a morphogen in patterning vertebrate embryo. Photo-uncaging of caged cyclofen proves to be a novel and powerful tool to non-invasively manipulate tumor-associated gene expression. The work shown here could shed new light on cancer initiation and growth, and provide new tools for target validation and testing of novel anti-cancer drugs.

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