
STRUCTURAL NEUROBIOLOGY
Rozbesky Lab
Research Interests

Molecular Mechanisms of Axon Guidance
The formation of precise neural circuits is fundamental to nervous system function. During development, neurons extend axons that navigate through complex environments to reach their correct targets. This process, known as axon guidance, is tightly regulated by molecular cues that steer axons toward or away from specific regions, ensuring proper connectivity.
Axon guidance is orchestrated by extracellular guidance cues, their receptors, and intracellular signaling pathways. Key guidance molecules include semaphorins, netrins, ephrins, and slits, which interact with their respective receptors—plexins, DCC/UNC5, Eph receptors, and Robo proteins—to regulate cytoskeletal dynamics and membrane trafficking. These signaling pathways regulate axonal growth and navigation, ensuring the axonal growth cone reaches its precise synaptic partner.
Our long-term goal is to unravel the fundamental principles of cell guidance and neural circuit formation. Specifically, we seek to elucidate how guidance receptors interpret extracellular signals and translate them into intracellular responses that direct the growth cone’s movement, turning, or retraction.
Current Areas of Research
Our research focuses on the structural biology and molecular mechanisms of the MICAL family of cytoskeletal effectors, which function downstream of plexin signaling. MICALs regulate actin filaments through a unique redox-based mechanism, directly binding to and oxidizing specific actin residues. This oxidation weakens inter-subunit interactions, leading to filament disassembly. Unlike classical actin-severing proteins such as cofilin or gelsolin, which disrupt actin filaments through conformational changes, MICALs employ oxidation to modulate cytoskeletal dynamics. Despite their established role in actin regulation, the precise molecular mechanisms controlling MICAL activation and inactivation, as well as their broader impact on F-actin remodeling, remain incompletely understood.
Our key research questions include elucidating how MICAL activity is precisely switched on and off and how this activity influences the organization of the actin cytoskeleton. To address these challenges, we integrate protein crystallography and cryo-electron microscopy (cryoEM) to visualize the high-resolution structures of MICAL proteins and their assemblies. This structural approach is complemented by protein engineering, advanced light microscopy, mass spectrometry, and cell-based functional assays, allowing for a comprehensive understanding of MICAL function.
Our research is highly collaborative, involving strong links with both local and international research groups.



CryoEM structure of human MICAL1 and time-lapse TIRF microscopy illustrating MICAL1-induced F-actin depolymerization.