Curated Optogenetic Publication Database

Abstract: Embryonic cells must interpret morphogen signals that vary in both time and space, but the rules by which they decode these dynamics remain unclear. Here we combine optogenetics with human 2D gastruloids to define minimal WNT signaling rules for germ-layer patterning. We block endogenous WNT secretion to create a “blank canvas” and reconstitute signaling using light-gated LRP6. Systematic temporal scans reveal a narrow competence window when the onset and duration of WNT signaling specify mesoderm; this window is shifted by cell density and amplified by BMP priming, whereas identical WNT inputs outside it invert germ-layer order or generate alternative mesodermal subtypes. Using micromirror-based illumination, we restricted WNT activation to a mid-ring during this temporal window; combined with BMP4, this fully restored germ layer domains with boundaries sharper than those generated by ligand stimulation. Thus, precise spatiotemporal control of a single pathway is sufficient to optically rebuild germ-layer architecture and reveals WNT as a temporal morphogen.

Abstract: Macrophages measure the "eat-me" signal immunoglobulin G (IgG) to identify targets for phagocytosis. We tested whether prior encounters with IgG influence macrophage appetite. IgG is recognized by the Fc receptor. To temporally control Fc receptor activation, we engineered an Fc receptor that is activated by the light-induced oligomerization of Cry2, triggering phagocytosis. Using this tool, we demonstrate that subthreshold Fc receptor activation primes mouse bone-marrow-derived macrophages to be more sensitive to IgG in future encounters. Macrophages that have previously experienced subthreshold Fc receptor activation eat more IgG-bound human cancer cells. Increased phagocytosis occurs by two discrete mechanisms-a short- and long-term priming. Long-term priming requires new protein synthesis and Erk activity. Short-term priming does not require new protein synthesis and correlates with an increase in Fc receptor mobility. Our work demonstrates that IgG primes macrophages for increased phagocytosis, suggesting that therapeutic antibodies may become more effective after initial priming doses.

Abstract: The integrated stress response (ISR) is a conserved signaling network that detects aberrations and computes cellular responses. Dissecting these computations has been difficult because physical and chemical inducers of stress activate multiple parallel pathways. To overcome this challenge, we engineered a photo-switchable control over the ISR sensor kinase PKR (opto-PKR), enabling virtual, on-target activation. Using light to control opto-PKR dynamics, we traced information flow through the transcriptome and for key downstream ISR effectors. Our analyses revealed a biphasic, proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal outcomes. We then constructed an ordinary differential equation (ODE) model of the ISR, which demonstrated the dependence of future stress responses on past stress. Finally, we tested our model using high-throughput light-delivery to map the stress memory landscape. Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters. A record of this paper's transparent peer review process is included in the supplemental information.