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Tracks of expressing neurons shown aligning linearly.

What happens when a neurobiologist, a structural biologist and a biophysicist walk into a bar? Well, if the conditions are right, they’ll sit down, have a drink and forge connections capable of breaking new ground in molecular neurobiology.

“It’s all about making people understand and trust each other,” says Elena Seiradake, a professor in molecular biology at the University of Oxford.

That’s the goal, anyway, at the 2022 Molecular Neurobiology Workshop, hosted by the European Molecular Biology Organization (EMBO) and co-sponsored by the Institute for Protein Innovation (IPI).

Set beachside on the island of Crete, Greece, the close-knit conference — co-organized by Seiradake — aims to situate scientists in an environment that encourages personal connection and conversation with other researchers.

A woman stands with arms crossed.
Elena Seiradake, professor in molecular biology at the University of Oxford. Photo courtesy of Elena Seiradake.

“We need to talk to each other more,” she says, “so that we can really gain from each other’s expertise … and then also provide access to different methods so people aren’t limited by what’s in their lab.”

No single lens to neurobiology

Seiradake is well acquainted with the advantages of a multi-angle approach to neuroscience.

Since she was an undergraduate, she’s been endlessly curious about the “lens through which we see the world.” Back then, she read books on philosophy and wondered how internal processes and brain function shaped how people understood their surroundings.

As a Ph.D. student at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, she worked with virologist Stephen Cusack on the structural characteristics of adenoviruses. His lab instilled in her a love of science and a clear, methodical approach to research, she says. But her early interest in neurological function trumped that in virology.

“The brain is in many ways the final frontier,” she says.

She brought the lessons learned in Cusack’s lab to a collaboration with Andrew McCarthy, an EMBL structural biologist specializing in the structure of brain receptors. With the McCarthy lab, Seiradake studied how the crystal structure of Slit2’s fourth domain — one of four large leucine-rich repeat domains that comprise the ligand protein, Slit — results in homodimerization and potential binding with a linear polysaccharide, heparan sulfate. This linkage, she found, impacts signaling between Slit proteins and Roundabout (Robo) receptors, affecting guidance cues in neuronal and vascular development.

In 2008, she moved to the University of Oxford to work as a postdoctoral fellow with Yvonne Jones, one of structural neurobiology’s “biggest stars,” known for her work on the structures of mammalian cell surface receptors. At an EMBO workshop on Cell Biology of the Neuron in 2011, she met and began collaborating with world-class neurobiologist Rüdiger Klein of the Max Planck Institute for Biological Intelligence. For the first time, Seiradake realized the power of cross-disciplinary collaboration and proceeded to publish seminal papers combining results from both labs.

By the end of 2014, Seiradake had developed her own research team in the Oxford Department of Biochemistry to unravel molecular mechanisms in the nervous and vascular systems. In 2020, she rose to the role of professor, determined to build knowledge around the specialized proteins that assist in the formation of these complex tissues.

People gathered around a table with plates and glasses for dinner.
The Seiradake Lab at the University of Oxford gathers for Christmas dinner. Photo courtesy of Elena Seiradake.

Breaking down the silo walls

It was at a neuroscience conference in 2016 that Seiradake realized the full impact isolated research was having on her field.

She was sitting in the corner of the conference hall with IPI’s antibody platform director, Rob Meijers — who was then a group leader working on neuronal receptors at EMBL Hamburg. Both were frustrated by the scarcity of attention paid to structural biology and neurobiology. Instead, researchers were focused on mapping synapses and neurons to track how neural circuits convey information and direct behavior.

“But on the molecular level, I think [circuit mapping] doesn’t tell us how we get there,” Seiradake says.

From her perspective, the molecular processes that underlie that circuitry play a pivotal role in neural function. Molecules work in tandem to affect brain plasticity and impact the assimilation of new knowledge. They’re a cipher to understanding how the brain works.

She and Meijers saw that ingrained research silos were preventing cross-disciplinary collaboration.

But what if there was a way to open up the field? What if they could foster connections between a diversity of research interests, specifically to focus on the molecular aspects of neurobiology?

“We thought we needed a new conference,” she says.

So they built it.

The inaugural EMBO Molecular Neurobiology Workshop launched in 2018. Four years later, they’ve seen it work its magic. More than one publication in recent years can trace its history back to the rocky shores of Crete, including high-impact studies on the structure and function of key cell surface receptor integrin alpha-5 beta-1 (α5β1), the use of synthetic synaptic organizer CPTX to repair damaged neuronal circuits, and the formation of a functionally-diminished super-complex composed of a cell surface receptor, neogenin (NEO1), and two opposing ligands.

From Crete to collaboration

Schematic of Teneurin, Latrophilin, and FLRT domain architecture.
Image: “Schematic of Teneurin, Latrophilin, and FLRT domain architectures” by del Toro, D. et al.

At the same 2018 conference, Seiradake, Klein and the talented postdoc Daniel del Toro, now a group leader in cortical neurodevelopment at the University of Barcelona, set in motion a project that would detail the role of three proteins — fibronectin leucine-rich transmembrane proteins (FLRTs), teneurins and latrophilins — in cortical neuronal migration during central nervous system development. Their results were published two years later in Cell.

FLRTs, single-spanning type I transmembrane proteins known to be expressed by migrating cortical neurons, had been previously established as a player in cell adhesion and receptor signaling by the Klein Lab.

Latrophilins, a group of mechanosensitive adhesion G protein-coupled receptors (GPCRs) first identified by their ability to bind to latrotoxin, or black widow venom, had been linked to neurodevelopmental disorders, such as ADHD. They were also found to be expressed by apical progenitor cells, which act as a highway for neuron migration.

Teneurins, large single-pass transmembrane proteins expressed in neurons, were known to act as key regulators of synaptic wiring and mark risk loci in bipolar disorder and schizophrenia. But as highly conserved glycoproteins, with evolutionary origins in unicellular organisms without a nervous system, teneurins were theorized to play a secondary role in cell adhesion.

“We have relatively few genes and relatively few receptors, and yet you get a brain which is so incredibly complex,” she says. “They come together in different arrangements that mean different things to the cells.”

Using X-ray crystallography and molecular dynamic simulations, the group uncovered the structural mechanism of how teneurin binds to latrophilin: latrophilin clamps on to separate binding motifs spread across tiers of the spiraling β-sheet of teneurin’s YD shell.

When latrophilin is present, the team determined, teneurin and FLRT bind around its N-terminal domains. The proteins form a trimeric complex, with latrophilin sandwiched in the middle.

A ternary complex formed by Teneurin and FLRT binding around Latrophilin's N-terminal domains.
Superposition of FLRT2 leucine-rich repeat domain produces a model of the ternary complex as shown. Image: “Crystal Structures of the Teneurin-Latrophilin Complex” by del Toro, D. et al.

Coupling structure-based protein engineering to biophysical analysis, cell migration assays, and in utero electroporation experiments, the team went on to probe the importance of the molecular trio’s interaction in cortical neuron migration. The researchers showed that the binding of latrophilins — produced by radial glial cells — to teneurins and FLRTs — co-expressed by migrating cortical neurons — directs the migration of those neurons during development.

Surprisingly, this ternary interaction, enacted in trans, involved a repulsive mechanism. The finding was in stark contrast to the typical adhesion of the proteins during synapses. This repulsion remolds the cytoskeleton, slows the migration of young neurons and enables downstream cell signaling.

Upper left: Images taken every seven minutes show dissociated cortical neurons forming clusters over time and being repelled from Lphn1-containing red stripes. Lower left: The tracks of individual cells (small gray circles) and the formation of cell clusters (indicated by bigger circles) are shown. Upper right: The tracked cells and clusters on the stripes used in the quantification at lower right. Lower right: The percentage of tracked neurons on Lphn1-containing stripes shows a reduction of neurons on these stripes over time. Video: “Time-Lapse Analysis of Dissociated Cortical Neurons on Lphn1 and Lphn1TL-FL Stripes” by del Toro, D. et al.

“It just shows that proteins can do many things; it’s context-dependent,” she says. “It just depends who else is around to signal with.”

For Seiradake, the study also demonstrated a similar phenomenon playing out on a much larger scale: Researchers can accomplish many things — much more than even they thought possible — it just depends who else is around to collaborate with. The sum is often greater than its parts.

“We have so many new techniques to do particular things, it’s changing how people do research,” she says. “There’s just a lot more collaboration that can happen now.”

Writer: Caitlin Faulds, caitlin.faulds@proteininnovation.org
Sources: Elena Seiradake, elena.seiradake@bioch.ox.ac.uk;
Rob Meijers, rob.meijers@proteininnovation.org

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