Thread by @Planaria1

Our @ScienceStowers lab's most recent effort to understand regeneration has just been published @ScienceMagazine.

science.sciencemag.org/content/369/65…

The story began sometime in 2008 with an idea after hearing Anne Brunet @BrunetLab give a talk at my old institution @UUtah

I wondered whether we could exploit the remarkable qualities of killifish, such as genetics, diapause, and rapid maturation, to study vertebrate adult regeneration?

In 2009, I visited @Stanford to give a seminar & had a chance to talk to Anne @BrunetLab & Dario Valenzano @darissambaya about killifish. I asked if killifish could regenerate. A few months later, Anne would let me know that, like zebrafish, killifish could regenerate their tails

In 2013, I met Wei @weiwang0128 when he was one of the students in the Embryology course @MBLScience.

At the time, Wei was working with drosophila.

And yes, Embryology won the softball game against the Physiology course @MBLPhysin that year, in case you were wondering...

In 2014, Wei approached me for a postdoctoral position. He wanted to work on regeneration in planarians. After interviewing him and discussing his interests, somehow I managed to convince him to venture with me in trying to develop the killifish to study regeneration.

When Wei accepted to embark with me on this adventure, I asked Anne in 2014 if I could visit her lab & spend a few days playing with killifish.

In September, I visited and learned a lot from another past embryology student Chi-Kuo Hu @ChiKuoHimself other @BrunetLab members

Back in Kansas City, we identified in 2015 a small room @ScienceStowers to set up a killifish colony, which we started from diapause embryos mailed to us by @BrunetLab

These embryos were grown first in the lab I keep adjacent to my office & later seeded the completed facility.

In June of 2016, just a year later, Wei began to generate his first CRISPR/Cas9 mutants (Tyrosinase -/-)...

In the same year, Wei also managed to get ChIP to work robustly in killifish, which allowed the identification of shared and unique epigenetic marks during tail regeneration in both killifish and zebrafish...

And in 2017, Wei began to clone enhancers and generate transgenic lines, providing evidence that the approach we had taken to identify putative regeneration enhancers was yielding useful data

In 2018, Wei and I spent many hours pouring over his data & discussing his results, including the AP-1 motif–enrichment of all detected elements.

Our goal was to identify and test multiple ways to prove our hypotheses wrong.

By 2019, we knew we had defined a powerful comparative approach to not only identify regeneration-response elements but also to identify species-specific vs. evolutionarily conserved responses.

Altogether, our data has led us to propose that the ancestral function of AP-1 motif–enriched enhancers was to respond to injury, any injury, by launching a regenerative response rather than just a wound-healing response.

In the course of evolution and speciation, regeneration and injury responses became dissociated from each other in some, but not all, enhancers.

In extant species, regeneration-competent animals maintain the ancestral enhancer activities to activate both injury response and regeneration, whereas repurposing of ancestral enhancers in regeneration-incompetent animals led to loss of regenerative capacities.

Clearly, there is still much we do not understand, and even much more work to do. But I believe the model above is eminently testable and I anticipate that by doing so, we will gain a much more precise understanding of the mechanisms underpinning animal regeneration.