Active Cells, Biochemistry & Physiology Genetics & Molecular Biology

Molecular interactions of guidance receptors acting in early cortical development

Funder Wellcome Charity-funded
Associated organisations University Medical Center Gottingen · Universitat de Barcelona · University of Oxford Europe PMC affiliations are not treated as award recipients or mapped locations.
Funding £4.2M
Period Apr 2023 — Mar 2031

In plain English

AI plain-English summary

A developing brain builds its layered cortex by guiding newborn neurons on a precise journey from their birthplace to their final position—and this project will map the molecular handshakes that direct that journey, one protein interaction at a time. The problem is that we know neurons must migrate in an orderly fashion to form the brain's six-layered structure, but we do not understand how specific receptor-ligand pairs, particularly the Unc5 receptors and their FLRT partners, control the timing and direction of that movement. Without this molecular-level map, we cannot explain why migration sometimes goes wrong in neurodevelopmental disorders. This is fundamental curiosity-driven science. The researchers will use structural biology, protein engineering, and mouse models to determine where and when these protein complexes form, solve their atomic structures, and design mutants that disrupt specific interactions. If successful, the work will provide a mechanistic blueprint for how guidance receptors orchestrate cell migration in the developing cortex. While there is no immediate practical application, similar fundamental studies of cell guidance molecules have previously illuminated how cancer cells metastasise and how nerve injuries might be repaired—so a deeper understanding of these molecular conversations could eventually inform regenerative medicine or developmental biology.

View original technical description
The development of a layered cortex requires tightly regulated cell migration events. These are controlled by context-dependent interactions of cell guidance receptors and their ligands, which occur between migrating cells and their environment. In this project, we focus on Unc5 guidance receptors and their FLRT ligands, which together with further binding partners, form combinatorial interactions that instruct the radial migration of neurons in early cortical development. We will assemble a detailed spatiotemporal map of when/where different protein complexes form during radial migration, determine their atomic structures to obtain mechanistic insight, and design structure- based mutants to specifically target combinatorial ligand binding in vitro and in vivo using mouse models. These results will establish a molecular-level understanding of how radial migration is determined by these guidance receptors. Research questions: - Where are different receptor interactions established during cortical migration? - What are the structural principles that control their interactions? - How do these interactions direct specific cellular behaviours during radial migration? The proposal presents an integrated work package using structural biology, protein engineering, proteomics, cell biology, advanced imaging and mouse in vivo technology. The project creates an outstanding interdisciplinary and international training environment for early career researchers to develop independent academic careers.

View the original record at the funder ↗

Researchers

Daniel del Toro (EPMC Awardee)Elena Seiradake (EPMC Awardee)Lindsay Baker (EPMC Awardee)Valentin Nägerl (EPMC Awardee)

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Original classification

Discovery Award

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