Robust axonal branch patterning through stochastic filopodial dynamics

• Applicant: Professor Dr. Peter Robin Hiesinger
• Subject Area: Developmental Neurobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 453877723

Brain wiring relies on specific axo-dendritic patterns, yet many aspects of these patterns differ between individuals. Dorsal Cluster Neurons (DCNs) are contralaterally projecting neurons in both brain hemispheres that exhibit a stereotypic projection pattern of known functional importance, as recently characterized by a team of RobustCircuit PIs. We call this pattern stereotypic, because relative axon and branch spacing and ratios are reproducible, while individual axon position and axonal branching positions and angles are more variable. Remarkably, this axonal projection pattern is robust to stochastic variations in the number of neurons on both sides of the brain. How does the developmental process ensure a stereotyped axonal targeting and branching pattern independently of the highly imprecise number of neurons that provide the axons and branches? We hypothesize a sequence of two competitive selection processes based randomly exploring filopodia. First, axon selection occurs based on Notch signaling-dependent axonal competition; second, axonal branch patterning occurs based on an EGFR signaling-dependent feedback mechanism between synapse formation and branch stabilization. Both mechanisms require stochastic dynamics to generate a pool of variability for competitive selection. The outcome ensures robust patterns of innervation on the left and right side of the brain that are both independent of each other and which are robust to stochastic variations in neuron numbers on each side of the brain. The approach of P2 is a quantitative investigation of axon and branch dynamics and outcome robustness based on advanced multi-photon intravital and ex vivo imaging techniques that have been established for DCNs in preparation for RobustCircuit. When these studies are concluded, we will have established a complete 4D dynamics profile and mechanistic basis for the development of a robust axonal targeting and branching pattern based on stochastic dynamics in an intact brain.

• DFG Programme: Research Units
• Subproject of: FOR 5289: From Imprecision to Robustness in Neural Circuit Assembly
• International Connection: France
• Cooperation Partner: Professor Dr. Bassem Hassan