Molecular mechanisms of neural circuit formation
An important step during neural circuit formation is the extension of axons to their target cells, where they form synapses. Axonal pathfinding is determined by a well-orchestrated cooperation of attractive and repulsive signals derived from the interaction between molecules in the environment of the extending axon and receptors concentrated on its tip, the growth cone. On their way to the target, axons contact one or several intermediate targets, or choice points. At each one of them, they need to switch their behavior from attraction to repulsion in order to move on. At the molecular level, this is achieved by a change in guidance receptors on the growth cone surface.
We use the floor plate, the ventral midline of the spinal cord in mouse and chicken embryos as a model to study the molecular mechanisms of axon guidance at a choice point. The crossing of the midline by commissural axons and their subsequent turn along the contralateral border of the floor plate provides a convenient readout for the effect of manipulations of gene expression in either the axons or the floor plate in vivo. Because molecular mechanisms of axon guidance are conserved throughout the nervous system, axonal midline crossing represents a relatively simple system to study mechanistic aspects of axon guidance. Using this system, we have identified axon guidance cues and their receptors that allow axons to enter and cross the floor plate, but also molecules that are important for the rostral turn of post-crossing axons. In particular, the precise temporal control of our loss of gene function studies has identified morphogens, molecules previously associated with cell differentiation and tissue patterning, as axon guidance cues for post-crossing axons.
Our current focus is on regulatory mechanisms that explain the smooth transition of axons from attraction to repulsion from the intermediate target. We have shown that receptor expression on the growth cone surface is altered in a tightly regulated manner by changes in transcription or trafficking. Furthermore, switches in growth cone behavior are induced by differences in protein-protein interaction preferences between molecules on the axon (cis-interactions) and between molecules on the axon and the floor plate (trans-interactions).
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Frei JA, Andermatt I, Gesemann M, and Stoeckli ET. (2014) The SynCAM synaptic cell adhesion molecules are involved in sensory axon pathfinding by regulating axon-axon contacts.
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Wilson NH and Stoeckli ET. (2013) Sonic hedgehog regulates its own receptor on postcrossing commissural axons in a glypican1-dependent manner.
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