Thread by @BrainOrganoid

📢New Lancaster Lab paper out now! Check it out, we've discovered a cool way evolution has played with cell shape to make our brains BIG! 🧵 cell.com/cell/fulltext/…

This is a question I've been interested in since starting my lab 6 years ago. And so this paper is a really big deal for me and the lab! So where to start...
We know that the human brain is about 3 times bigger than chimps' and gorillas' but why? How?

We can't (nor would we want to) do experiments on developing ape brains, so we approached this question by using brain organoids, little pea-sized replicas of early brain tissue. And when we made organoids from different apes, there was a clear difference in size!

So now the question was, why? We looked earlier in organoid development and found a clear difference in cell shape, with very early progenitors called neuroepithelial cells that were staying "fat" for longer in human.

We then found that while these cells were fatter in human, they also had a faster cell cycle. This means that the progenitors could increase more in that time in humans, giving us a bigger founder population to start with. Thanks to Kate McDole for CRAZY COOL imaging!

Then the question was, what's triggering this change in cell shape and why is it happening more slowly in human? This is where RNA-seq came in and identified ZEB2, a key regulator of epithelial to mesenchymal transition.

So we functionally tested ZEB2 by perturbing its expression and its downstream signaling in several ways, and found that it can trigger this transition earlier in human if it's turned on earlier. Cool right?

Then we also tested the opposite, and inhibited the effects of ZEB2 downstream by treating with Bmp, and could see "fatter" cells in the gorilla. So confirming its role in helping drive the timing of this transition!

Overall, we've identified this cool new transition state, that is delayed in humans, and leads to increased organoid size, in line with the difference you see in actual brains.

This was a HUGE amount of work, done by @silviakima and Stefano Giandomenico, with a lot of help from Magda Sutcliffe and @Dabrica in the lab, and our amazing collaborators! Thanks to them all!