Perspectives: Family and Fate of a Neuron
Tracing cells' pasts and predicting their progeny
Every cell has a past: ancestors whose genes and adaptations are passed down over many generations to shape the cell’s identity, its activity as part of a larger organism, even its ability to survive. Tzumin Lee knows that uncovering this past is essential for understanding not just how the cell came to be, but what more it could become.
Lee explains how his lab at the University of Michigan Life Sciences Institute is developing tools to trace cells’ ancestral pasts and predict their progeny — with the goal of revealing the processes that turn a single stem cell into complex tissue and how those processes might be harnessed to regenerate damaged cells and tissues. (Interview edited for clarity and length)
How did you get started in this line of investigation, looking at cell lineage and cell fate?
I am curious about developmental biology. Initially, I wanted to understand how the genome can encode a complex tissue. Every cell in an organism contains the same genome, the same code, and yet that code results in an enormous variety of cell types. The most complex tissue in the body is the brain, so I started out with the question: How can the genome create a complex organ like the brain?
I began to answer this question using Drosophila [fruit flies], because their development is much more trackable. Because the genome is passed on through cell lineage, we started with tracking cell lineage. Through this work, we came to understand a lot about how the fly brain developed, and we started to uncover some of the molecular mechanisms that drive brain development in flies.
But in that process, I also discovered that cell lineage is much more important than I had thought. I realized that without knowing the cell lineage, I wouldn’t be able to figure out the detailed mechanisms of development.
When you say you found cell lineage to be more important than you expected, why do you think that is the case?
When I started out, even I didn’t believe cell lineage controlled everything. I thought it would just set a foundation, and then many subsequent events would refine the cell type. But that turns out to be not true. Cell lineage dictates cell fate. It is the blueprint for the development of an entire organism, including the brain.
In the complex nervous system, every neuron has a unique form and function. It is striking to see how every neuron knows what it should do based on its origin — both the neuronal stem cell it originated from as well as its birth order.
One neuronal stem cell can produce multiple neurons in a long sequence. There are 100 neuronal stem cells in Drosophila, for example, and each one divides roughly 80 to 120 times. Every Drosophila neuron knows what it should do in the complex brain based on which neuronal stem cell it arose from and then also whether it was the first neuron produced, the second or the hundredth.
Tracking the cell lineage back to its origins allows us to see the cellular processes that enable 100 cells to develop into an entire nervous system. If you don’t resolve the lineage of each cell, you won’t be able to appreciate such stereotyped patterns of neurogenesis and cannot figure out how one genome creates this vast diversity of cells in complex tissues.
Cell lineage dictates cell fate. It is the blueprint for the development of an entire organism, including the brain.
In addition to this backward tracing — finding where each neuron originates — your lab also looks forward to predict what stem cells will become, right?
That’s right. In flies, we started with the retrospective approach because we had tools that we could use for that. But now, with technologies like single-cell RNA sequencing and CRISPR gene editing, we can also look prospectively, from a stem cell to its progeny. Now we are tracking both retrospectively and prospectively in both flies and vertebrates. Ultimately, we plan to connect the cell lineage information and the developmental trajectory to map the true cell lineage in both directions and reveal the gene dynamics directly. This is particularly crucial for the tracking of many more neuronal lineages in vertebrate brains.
How have technological developments and new tools allowed your research program to tackle cell lineage in both directions?
One major development that allowed our approach to evolve is single-cell genomics. We can now sequence the output of the genome at the single-cell level. Every cell in an organism has the same genome, but the genome’s output is different across different cells. We can profile those outputs now, which we couldn’t do when I started.
That advancement, along with the CRISPR gene-editing technology, has allowed my lab to build more powerful tools for lineage tracing. During my postdoctoral research, I developed a tool that allowed us to discover the functions of genes and trace the lineages of neurons by random clonal labeling. Then, while I was at the HHMI’s Janelia Research Campus, we were able to incorporate CRISPR into tools for targeting and labeling specific lineage branches. This allows us to target specific neural progenitors based on multi-gene expression patterns and then track the lineages with the serially derived neurons labeled in distinct colors based on birth order. We can now map neuronal lineages with fine temporal resolution, both prospectively and retrospectively.
What’s next for your lab at the University of Michigan?
At the LSI, we’re building new facilities to combine cell lineage, single-cell genomics and the CRISPR technology. My vision is to track and tailor genome output along cell lineage to unravel how the genome guides brain development. Comparing this developmental process across species would inform us how to steer brain development. So our research extends from fly to fish and mouse and, finally, hopefully, to a human brain organoid.
Given that this ambition is far beyond what a single lab can possibly achieve, I’m excited to be at the University of Michigan. With the medical school located so close to the academic campus, and the LSI connecting them, I hope to team up with many labs to push the science forward together. We aim to enable new biomedical research for many to follow. We can then keep working on new things and moving on to the next challenge.