Extrinsic mechanical forces mediate retrograde axon extension in a developing neuronal circuit

Abstract

To form functional neural circuits, neurons migrate to their final destination and extend axons towards their targets. Whether and how these two processes are coordinated in vivo remains elusive. We use the zebrafish olfactory placode as a system to address the underlying mechanisms. Quantitative live imaging uncovers a choreography of directed cell movements that shapes the placode neuronal cluster: convergence of cells towards the centre of the placodal domain and lateral cell movements away from the brain. Axon formation is concomitant with lateral movements and occurs through an unexpected, retrograde mode of extension, where cell bodies move away from axon tips attached to the brain surface. Convergence movements are active, whereas cell body lateral displacements are of mainly passive nature, likely triggered by compression forces from converging neighbouring cells. These findings unravel a previously unknown mechanism of neuronal circuit formation, whereby extrinsic mechanical forces drive the retrograde extension of axons.

Role of mechanical cues in shaping neuronal morphology and connectivity

“…The maximum tension was measured on cell/cell interfaces located in the centre of the tissue, perpendicular to the brain surface (Figure c, orange arrow), which is the direction of the passive cell body movements during axonal elongation (Figure b, orange arrow). This map further supports the idea that the cell bodies of the olfactory neurons undergo compression or traction forces (Figures c and d, green arrows) driving their passive movement and the retrograde extension of axonal processes (Figure d) [Breau et al., ]. Future experiments will identify which cells or tissues generate the mechanical forces driving axon extension in this system.…”

“…Indeed an elegant study reported that the primordium provides cues ensuring the growth and guidance of the sensory axons [Gilmour et al., ], but it remains unclear whether the migrating primordium mechanically tows the axons through adhesion mechanisms, or serves as a source of chemical cues guiding the growth cones of the axons. Recently, our laboratory discovered that axon growth mediated by extrinsic forces can occur during the early stages of axon elongation in vivo [Breau et al., ]. Using live imaging, we analysed the dynamics of neuronal movements and axon formation in the zebrafish sensory olfactory circuit, which assembles during the morphogenesis of the olfactory placode.…”

“… Extrinsic mechanical forces mediate retrograde axon extension in the zebrafish olfactory circuit [adapted from Breau et al., ) ( a ) Time lapse imaging showing the behaviour of a neuron undergoing retrograde axon extension in the zebrafish olfactory placode. The white line delineates the brain surface.…”

“…While most studies unravelled a role for mechanical forces on neuronal development in vitro , functional evidence demonstrating the in vivo importance of mechanical inputs has only started to emerge. Such investigation has long been technically challenging but now becomes feasible owing to recent progress which allows the combination of in vivo imaging with physical approaches to probe and perturb mechanics in developing neural tissues [Koser et al., ; Breau et al., ]. Future work will be crucial to understand how developing neurons perceive and transduce mechanical inputs into signalling pathways.…”

“…Figure was adapted from Breau et al. () (Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0).…”