ditalialab.bsky.social
Quantitative Developmental Biology @Duke
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Congrats, this looks really cool.
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Also thanks to the @kitp-ucsb.bsky.social for supporting Woon during his stay in Santa Barbara to perform a lot of the work that went into the paper
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Thanks, Carole!!
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Thanks!
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Collectively, our work leads to a new paradigm for the control of positional memory during regeneration. The Fgf20a source encodes the amount of tissue removed and controls a cellular program that ensures the decay and scaled expansion of Erk gradients which in turn control tissue growth
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Furthermore, we also showed that the number of Fgf20a producing cells is predictive of tissue outgrowth in mutants (longfin mutants) in which memory of tissue size is lost.
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Next, we turned our attention to the ligand producing source and specifically to the cells of the basal epidermis that produce Fgf20a, which is upstream in the regeneration cascade and absolutely required. We found that the number of Fgf20a producing cells scale with the amount of tissue removed.
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We supported the first condition by experiments blocking protein synthesis and estimating that Erk activity is retained at normal levels for at least 12 hours (longer inhibition were toxic) arguing for a lifetime of few days.
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Two conditions have to be met for the model to work. First, the lifetime of the ligand controlling the gradient must be 4 days or longer. Second, the size of the source region (at the tip of the regenerate) producing the ligands must scale with the amount of tissue removed.
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Based on several estimates, we concluded that diffusion was unlikely to play a major role in the establishment of the gradients. Thus we focused on the role of advection (transport) of ligands by tissue growth and found that such a model could perfectly explain our data
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An interesting property of these gradients is that they can be thought of as rulers measuring how much growth has occurred and how much is still left to occur. But how are these gradients built? In collaboration with Massimo Vergassola, we developed a mathematical model for the gradients
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To be more clear, this is the behavior of the gradients across space and time
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This framework has several interesting consequences, implying that average Erk activity is what encodes memory of tissue size, while the Erk gradients have invariant properties, i.e. the ratio of Erk activity at the tip vs the amputation plane is the same for all rays at all times.
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This led us to ask how Erk activity is controlled in space and time. We realized that Erk activity can be described mathematically throughout the entire regeneration process as the product of two functions, one describing time-dependency (left) and one spatial-dependency (right)
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By quantifying Erk activity and proliferation in all osteoblasts of the regenerate, we found that Erk activity is predictive of the probability of cells to proliferate independently of the amount of tissue removed
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To understand how this scaling is encoded, we turned our attention to Fgf/Erk pathway as it has a well established role in controlling growth in many contexts, including fin regeneration. To characterize the spatiotemporal dynamics of the pathway, we use the Erk biosensor to measure activity.
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We then went on to demonstrate that proliferation perfectly scales when different amounts of tissue are removed by amputation, so that the probability of proliferation depends only on fraction of tissue that has regenerated.
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Using quantitative approaches, we first demonstrated the tissue growth is mainly controlled by the proliferation of existing osteoblasts.
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Here we asked how the memory of bone size is encoded during zebrafish regeneration. This process nicely illustrates the concept of positional (geometric) memory, that is the ability of the regenerating fin to grow back to its pre-injury size and shape.
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Thanks, Woon. Yours is next ;)
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It was so much fun to work with your group. More to come!
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Thanks, Aleks!
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Most notably, we found a quantitative relationship (previously unknown to the best of our knowledge) between the speed of chromosome movement and the rate at which nuclei complete anaphase (likely set by the rate of dephosphorylation of mitotic targets). Excited to see if this is conserved.
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While the cell cycle is the dominant mechanism controlling chromosome speed, careful data analysis suggests residual contributions from spindle length through mechanisms that remain to be elucidated at this point.
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Yitong discovered that there is a tight correlation between the speed of chromosome separation and the duration of anaphase and that in turn this duration is mainly set by the activity of mitotic kinases Cdk1 and Polo and the mitotic phosphatase PP2A-B55.
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Consistently with this, we found that several motors involved in MT depolymerization could all impact chromosome speed when their amounts were genetically reduced. This pointed to a possible global regulator of MT dynamics and we turned our attention to the cell cycle.
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Yitong discovered that both the speed of chromosome movements and spindle size scale with the space available to nuclei in the blastoderm embryo. The scaling of chromosome speed correlated with the poleward flux of microtubules, arguing that it might be controlled by the rate of MT depolymerization.
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Happy Birthday!
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Congrats, Andi!
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Sometimes you fry the abomination (if you are in a certain region of Italy, that is)
en.wikipedia.org/wiki/Gnocco_...