The bright future of developmental biology

Summary by Cat Rogers: Johnson, H. E. & Toettcher, J. E. Illuminating developmental biology with cellular optogenetics. Curr Opin Biotechnol 52, 42-48, doi:10.1016/j.copbio.2018.02.003 (2018). & Rogers, K. W. & Muller, P. Optogenetic approaches to investigate spatiotemporal signaling during development. Curr Top Dev Biol 137, 37-77, doi:10.1016/bs.ctdb.2019.11.009 (2020).

Image credit: Robert D. Anderson, Wikimedia Commons

Healthy development depends on morphogen signaling to control when and where genes are expressed in the embryo. A given signaling molecule can have different effects on cell fate decisions depending on its concentration, dynamics, history, and context. While there have been dramatic advancements in observation and quantification of fate decisions, their underlying mechanisms are still incompletely understood. Techniques to precisely perturb systems and explore mechanisms in detail are needed. Optogenetic tools bring tunability, spatiotemporal precision, and reversibility to the next level.

Molecular optogenetics tools repurpose naturally occurring light-responsive domains (LRDs) to provide experimental control over a variety of biological processes. For example, optogenetic tools have been used to modulate gene expression, signaling pathway activity, and enzyme activity. Some tools affect activity by regulating localization, recruiting a molecule to or sequestering it from its typical location of activity.1,2 Other tools cluster molecules, bringing them together to interact or to prevent external interaction.1,2 Others modulate a protein’s function by introducing light-dependent structural modifications.2 Coupling different effectors with LRDs therefore offers many strategies to control diverse biological processes.

Researchers’ limited control over techniques like heat shock and chemical inducers makes it difficult to tune amount of activity, reverse activity, and induce activity with spatial precision. Molecular optogenetics addresses these limitations. With optogenetics, varying light intensity translates to varying levels of expression or activity.2-4 With reversible optogenetic tools, varying the timing and duration of light exposure translates to varying the timing and duration of expression or activity. For spatial control over expression and activity, researchers simply manipulate the location and distribution of light.4 Using light as a remote control for biological processes gives researchers flexibility that has not previously been feasible.

This control and range of manipulable variables in one tool allows researchers to explore responses to signaling in more detail. An outstanding question is how sensitive a system is to specific spatial distributions of signals. Optogenetic tools can allow researchers to manipulate signal distributions across an embryo at cellular resolution.2,4,5 In addition to signal location, molecular optogenetics allows researchers to explore responses to the timing of signaling4,6-8 and how different signal dynamics (e.g., pulsatile vs. continuous)5,9 affect cellular responses. Further, to understand how embryos deal with intrinsic variation, optogenetics provides a precise strategy to experimentally create variability to observe cell adaptations.2,10-14

The future of developmental biology in light of optogenetics is bright. Perturbing the source, movement, and range of a molecule with optogenetic tools can reveal how signaling molecules spread through tissues.2 Further, optogenetic tools responsive to different wavelengths can orthogonally modulate distinct signals to explore how signals interact in multiplexes.2 Although promising, there is work to be done to improve their transferability from system to system and avoid crosstalk between optogenetic activation and fluorescent protein reporting. As researchers improve existing tools, develop new ones, and begin to make transgenic optogenetic systems, our understanding of developmental mechanisms is poised to accelerate and diversify significantly.

References:

1. Johnson, H. E. & Toettcher, J. E. Illuminating developmental biology with cellular optogenetics. Curr Opin Biotechnol 52, 42-48, doi:10.1016/j.copbio.2018.02.003 (2018).

2. Rogers, K. W. & Muller, P. Optogenetic approaches to investigate spatiotemporal signaling during development. Curr Top Dev Biol 137, 37-77, doi:10.1016/bs.ctdb.2019.11.009 (2020).

3. Rogers, K. W., ElGamacy, M., Jordan, B. M. & Muller, P. Optogenetic investigation of BMP target gene expression diversity. Elife 9, doi:10.7554/eLife.58641 (2020).

4. Johnson, H. E. et al. The Spatiotemporal Limits of Developmental Erk Signaling. Dev Cell 40, 185-192, doi:10.1016/j.devcel.2016.12.002 (2017).

5. Johnson, H. E. & Toettcher, J. E. Signaling Dynamics Control Cell Fate in the Early Drosophila Embryo. Dev Cell 48, 361-370 e363, doi:10.1016/j.devcel.2019.01.009 (2019).

6. Reade, A. et al. TAEL: a zebrafish-optimized optogenetic gene expression system with fine spatial and temporal control. Development 144, 345-355, doi:10.1242/dev.139238 (2017).

7. Sako, K. et al. Optogenetic Control of Nodal Signaling Reveals a Temporal Pattern of Nodal Signaling Regulating Cell Fate Specification during Gastrulation. Cell Rep 16, 866-877, doi:10.1016/j.celrep.2016.06.036 (2016).

8. Vopalensky, P., Pralow, S. & Vastenhouw, N. L. Reduced expression of the Nodal co-receptor Oep causes loss of mesendodermal competence in zebrafish. Development 145, doi:10.1242/dev.158832 (2018).

9. Wilson, M. Z., Ravindran, P. T., Lim, W. A. & Toettcher, J. E. Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control. Mol Cell 67, 757-769 e755, doi:10.1016/j.molcel.2017.07.016 (2017).

10. Sokolik, C. et al. Transcription factor competition allows embryonic stem cells to distinguish authentic signals from noise. Cell Syst 1, 117-129, doi:10.1016/j.cels.2015.08.001 (2015).

11. Aoki, K. et al. Stochastic ERK activation induced by noise and cell-to-cell propagation regulates cell density-dependent proliferation. Mol Cell 52, 529-540, doi:10.1016/j.molcel.2013.09.015 (2013).

12. Huang, A., Amourda, C., Zhang, S., Tolwinski, N. S. & Saunders, T. E. Decoding temporal interpretation of the morphogen Bicoid in the early Drosophila embryo. Elife 6, doi:10.7554/eLife.26258 (2017).

13. Toettcher, J. E., Weiner, O. D. & Lim, W. A. Using optogenetics to interrogate the dynamic control of signal transmission by the Ras/Erk module. Cell 155, 1422-1434, doi:10.1016/j.cell.2013.11.004 (2013).

14. Isomura, A., Ogushi, F., Kori, H. & Kageyama, R. Optogenetic perturbation and bioluminescence imaging to analyze cell-to-cell transfer of oscillatory information. Genes Dev 31, 524-535, doi:10.1101/gad.294546.116 (2017).