Project Details
Projekt
Stochastic early assembly as the molecular basis of robust active zone formation
Subject Area
Developmental Neurobiology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 453877723
During development, the formation of presynaptic active zones (AZs) - the structures controlling synaptic vesicle release - in the correct number, size, and spatial distribution is essential for establishing functional neuronal circuits. Although key molecular components of AZ scaffold assembly have been identified, it remains poorly understood how the system dynamically regulates AZ formation in response to intrinsic and extrinsic cues, such as developmental stage or environmental factors like temperature. Our recent work suggests that AZ formation follows a two-phase mechanism: an initial stochastic seeding phase followed by selective stabilization. Using intravital imaging of labeled Liprin-αEGFP in immobilized Drosophila larvae, we observed that seeding sites emerge and vanish within minutes, with only a subset progressing to recruit additional AZ components such as BRP and ultimately maturing. Complementary computational modeling (with Project Z, Reifenstein/Kleist, manuscript in preparation) supports the idea that adaptive modulation of stabilization rates, determined by cellular resource availability and competition, shapes the stereotyped mature AZ pattern. We propose that this regulatory logic, initially permissive and stochastic, followed by selective restriction, enables robust AZ patterning. Such a mechanism may confer resilience to developmental and environmental perturbations, for example temperature shifts, by allowing adaptive optimization of synapse formation. We have identified two major regulatory modules implicated in this adaptive process: (i) Myo15, a MyTH4-FERM domain-containing myosin that modulates the local cytoskeleton and possibly cargo distribution (Petzoldt lab) and (ii) the polarity kinases Par-1/aPKC which together with the PP1-Spinophilin complex and the newly identified Rab3-GAP Blobby ensure robust AZ maturation (Sigrist lab). These findings lead us to propose that synaptic robustness does not result from a strictly linear or deterministic program, but emerges through a coordinated interplay of partially redundant, yet interlinked regulatory modules. These act downstream of an initial stochastic seeding phase to filter, refine, and stabilize synaptic sites in an adaptive, context-sensitive manner.
DFG Programme
Research Units
