To move directionally, cells can bias the generation of protrusions or select among randomly generated protrusions. Here we use 3D two-photon imaging of chick branchial arch 2 directed neural crest cells to probe how these mechanisms contribute to directed movement, whether a subset or the majority of cells polarize during movement, and how the different classes of protrusions relate to one another. We find that, in contrast to Xenopus, cells throughout the stream are morphologically polarized along the direction of overall stream movement and do not exhibit contact inhibition of locomotion. Instead chick neural crest cells display a progressive sharpening of the morphological polarity program. Neural crest cells have weak spatial biases in filopodia generation and lifetime. Local bursts of filopodial generation precede the generation of larger protrusions. These larger protrusions are more spatially biased than the filopodia, and the subset of protrusions that are productive for motility are the most polarized of all. Orientation rather than position is the best correlate of the protrusions that are selected for cell guidance. This progressive polarity refinement strategy may enable neural crest cells to efficiently explore their environment and migrate accurately in the face of noisy guidance cues.
Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic...
Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic TFs are not currently pharmaceutically tractable due to their paucity of ligandable pockets. The first generation of transcription factor targeting chimeras (TRAFTACs) was developed to target TFs for proteasomal degradation by exploiting their DNA binding ability. In the current study, we have developed the second generation TRAFTACs (oligoTRAFTACs) comprised of a TF-binding oligonucleotide and an E3 ligase-recruiting ligand. Herein, we demonstrate the development of oligoTRAFTACs to induce the degradation of two oncogenic TFs, c-Myc and brachyury. In addition, we show that brachyury can be successfully degraded by oligoTRAFTACs in chordoma cell lines. Furthermore, zebrafish experiments demonstrate in vivo oligoTRAFTAC activity. Overall, our data demonstrate oligoTRAFTACs as a generalizable platform towards difficult-to-drug TFs and their degradability via the proteasomal pathway.
New research demonstrates that mechanics can serve as a means of information propagation in developing embryos. Historically, the study of embryonic development has had a dichotomy between morphogens and pattern formation on the one hand and morphogenesis and mechanics on the other. Secreted signals are the preeminent means of information propagation between cells and used to control cell fate, while physical forces act downstream or in parallel to shape tissue morphogenesis. However, recent work has blurred this division of function by demonstrating that mechanics can serve as a means of information propagation. Adhesive or repulsive interactions can propagate through a tissue as a wave. These waves are rapid and directional and can be used to control the flux of cells through a developmental trajectory. Here, two examples are reviewed in which mechanics both guides and mediates morphogenesis and two examples in which mechanics intertwines with morphogens to regulate cell fate.
The reproducibility of embryonic development is a remarkable feat of biological organization, but the underlying mechanisms are poorly understood. Clearly, gene regulatory networks are central to the orderly progression of development, but noisy molecular and cellular processes should reduce reproducibility. Here, we identify ergodicity, a type of dynamical stability, as underlying the reproducibility of development. In ergodic systems, a single timepoint measurement equals a time average. Focusing on the zebrafish tailbud, we define gene expression and cell motion states using a parallel statistical analyses of single cell RNA sequencing data and in vivo timelapse cell tracking data and a change point detection algorithm. Strikingly, the cell motion state transitions in each embryo exhibit the same patterns for both a single timepoint and a 2-3 hour time average. Both the cell motion and gene expression cell states exhibit balanced influx and outflux rates reflecting a spatiotemporal stability. Stated simply, these data indicate the pattern of changes in the tailbud doesn’t change. This ergodic pattern of cell state transitions may represent an emergent meta-state that links gene networks to the reproducible progression of embryogenesis.
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