Up close, a developing retina looks like a crowded railway station: nerve cells set off all at once, pass each other, turn back and choose surprising routes. And yet the result is a precisely layered tissue. For six and a half years, Caren Norden’s team watched this process in transparent zebrafish embryos and found that neurons follow signals from their neighbours, while some of their moves protect the maturing tissue – and at the end you can check how you find your own way in creative chaos.
Most neurons are born far from their final destinations. To build a functioning nervous system, these cells have to travel through tissue and, once they arrive, form working connections. In the retina and in other developing brain regions there is one more task: the cells must arrange themselves into distinct layers. Scientists call this process neuronal lamination.
Surprisingly little was known about how lamination happens in the retina. Most research had focused on the cortex, and it looked mainly at the migrating cells themselves rather than at the tissue around them. The ERC-funded project makingtheretina set out to change that, and over six and a half years it delivered a step change in understanding how the retina is formed.
The project worked with zebrafish, a well-established animal model that is ideal for observing lamination. The fish is small and transparent, it develops quickly, and its retina is relatively accessible compared with other parts of the central nervous system.
The key technique was long-term light-sheet microscopy. It illuminates one thin plane of tissue at a time, which is gentle enough to keep the embryos healthy for days. “Long-term light-sheet microscopy allowed us to watch cell migration and lamination in the zebrafish embryo as it happened,” says principal investigator Caren Norden, previously of the Gulbenkian Institute for Molecular Medicine and now at the University of Cambridge.
Watching cells for days produces a huge amount of images, so the biologists were joined by computer scientists and theorists. Together they combined the experiments with:
“Custom analysis tools allowed us to follow cell movements over time and extract speeds, directions and shape changes, revealing the distinct strategies used by the different retinal neuronal types,” Norden explains. The predictive tools and theoretical models helped the team generate hypotheses about what drives the movements, test them and then refine them in repeated rounds.
What the team saw at first looked like chaotic neuronal ‘traffic’. Underneath it, however, was exquisite dynamic control. “Our studies showed that precise tissue structure emerges from surprisingly messy behaviour. Different cell types move simultaneously using different strategies, often passing each other to reach their final locations,” says Norden.
In other words, there is no single, tidy queue. Several types of neurons are on the move at the same moment, each with its own way of travelling, and the precise layers appear only as the sum of all these journeys.
Horizontal cells are a good example. They did not follow fixed paths. Instead, each cell took its own unpredictable route. The researchers originally expected the physical structure of the tissue to guide them, but that was not the case.
The horizontal cells were guided by indirect cell communication – chemical signals coming from neighbouring cells. It is a bit like finding your way through a new city by watching and listening to the people around you rather than by following a painted line on the pavement.
The most surprising finding concerned photoreceptor cells. “Most strikingly, some neuronal movement serves to protect tissue maturation. Photoreceptor cells travelled back and forth, making a U-turn to temporarily clear the space where they would later reside so that neighbouring progenitor cells could finish dividing,” adds Norden.
So a move that looks like a mistake – going away from your future place and then coming back – turns out to have a purpose: it gives the neighbours room to finish their work. The same ‘space-making’ behaviour was observed in human retinal organoids, which suggests that it is a conserved biological strategy.
The project showed that the tissue structure of the developing retina and the moving cells continuously shape one another, while the forming tissue stays protected. Striking aspects of this were seen in human retinal organoids, and they may be present in other brain regions as well.
Future research will look at the molecular mechanisms behind each cell’s journey and at how robust neuronal lamination is, including the genetic link to specific chemical and mechanical cues in neural migration defects. That is where the medical stakes lie. “Faulty neuronal positioning underlies conditions like epilepsy and intellectual disability. By working out how neurons find their correct positions in the zebrafish retina, we are building the understanding needed to explore what goes wrong in neurological and neurodevelopmental disorders,” Norden concludes.
The makingtheretina project shows that a precise structure can grow out of what looks like disorder. Neurons in the developing zebrafish retina move at the same time, use different strategies, follow chemical signals from their neighbours and sometimes even turn back to make room for others. Model organism research still plays an essential role in understanding how tissues and organs develop in health and disease, and combining experiments with computational and theoretical tools deepens that understanding significantly.
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