Self-Wiring of Neural Networks

In order to form the intricate network of synaptic connections in the brain, the growth cones migrate through the embryonic environment to their targets using chemical communication. As a first step to study self-wiring, 2D model systems of neurons have been used. We present a simple model to reproduce the salient features of the 2D systems. The model incorporates random walkers representing the growth cones, which migrate in response to chemotaxis substances extracted by the soma and communicate with each other and with the soma by means of attractive chemotactic "feedback".Comment: 10 pages, 10 PostScript figures. Originally submitted to the neuro-dev archive which was never publicly announced (was 9710001

Neuropilin Is a Receptor for the Axonal Chemorepellent Semaphorin III

AbstractExtending axons in the developing nervous system are guided to their targets through the coordinate actions of attractive and repulsive guidance cues. The semaphorin family of guidance cues comprises several members that can function as diffusible axonal chemorepellents. To begin to elucidate the mechanisms that mediate the repulsive actions of Collapsin-1/Semaphorin III/D (Sema III), we searched for Sema III–binding proteins in embryonic rat sensory neurons by expression cloning. We report that Sema III binds with high affinity to the transmembrane protein neuropilin, and that antibodies to neuropilin block the ability of Sema III to repel sensory axons and to induce collapse of their growth cones. These results provide evidence that neuropilin is a receptor or a component of a receptor complex that mediates the effects of Sema III on these axons

Differences in protein mobility between pioneer versus follower growth cones

Navigating growth cones need to integrate, process and respond to guidance signals, requiring dynamic information transfer within and between different compartments. Studies have shown that, faced with different navigation challenges, growth cones display dynamic changes in growth kinetics and morphologies. However, it remains unknown whether these are paralleled by differences in their internal molecular dynamics. To examine whether there are protein mobility differences during guidance, we developed multiphoton fluorescence recovery after photobleaching methods to determine molecular diffusion rates in pathfinding growth cones in vivo. Actively navigating growth cones (leaders) have consistently longer recovery times than growth cones that are fasciculated and less actively navigating (followers). Pharmacological perturbations of the cytoskeleton point to actin as the primary modulator of diffusion in differently behaving growth cones. This approach provides a powerful means to quantify mobility of specific proteins in neurons in vivo and reveals that diffusion is important during axon navigation

beta1-integrin mediates myelin-associated glycoprotein signaling in neuronal growth cones

Several myelin-associated factors that inhibit axon growth of mature neurons, including Nogo66, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp), can associate with a common GPI-linked protein Nogo-66 receptor (NgR). Accumulating evidence suggests that myelin inhibitors also signal through unknown NgR-independent mechanisms. Here we show that MAG, a RGD tri-peptide containing protein, forms a complex with β1-integrin to mediate axonal growth cone turning responses of several neuronal types. Mutations that alter the RGD motif in MAG or inhibition of β1-integrin function, but not removal of NgRs, abolish these MAG-dependent events. In contrast, OMgp-induced repulsion is not affected by inhibition of b1-integrin function. We further show that MAG stimulates tyrosine phosphorylation of focal adhesion kinase (FAK), which in turn is required for MAG-induced growth cone turning. These studies identify β1-integrin as a specific mediator for MAG in growth cone turning responses, acting through FAK activation

Plexin A Is a Neuronal Semaphorin Receptor that Controls Axon Guidance

AbstractThe Semaphorins comprise a large family of secreted and transmembrane proteins, some of which function as repellents during axon guidance. Semaphorins fall into seven subclasses. Neuropilins are neuronal receptors for class III Semaphorins. In the immune system, VESPR, a member of the Plexin family, is a receptor for a viral-encoded Semaphorin. Here, we identify two Drosophila Plexins, both of which are expressed in the developing nervous system. We present evidence that Plexin A is a neuronal receptor for class I Semaphorins (Sema 1a and Sema 1b) and show that Plexin A controls motor and CNS axon guidance. Plexins, which themselves contain complete Semaphorin domains, may be both the ancestors of classical Semaphorins and binding partners for Semaphorins

Topographically specific effects of ELF-1 on retinal axon guidance in vitro and retinal axon mapping in vivo

Peer reviewedPublisher PD

Slit1 and Slit2 Cooperate to Prevent Premature Midline Crossing of Retinal Axons in the Mouse Visual System

AbstractDuring development, retinal ganglion cell (RGC) axons either cross or avoid the midline at the optic chiasm. In Drosophila, the Slit protein regulates midline axon crossing through repulsion. To determine the role of Slit proteins in RGC axon guidance, we disrupted Slit1 and Slit2, two of three known mouse Slit genes. Mice defective in either gene alone exhibited few RGC axon guidance defects, but in double mutant mice a large additional chiasm developed anterior to the true chiasm, many retinal axons projected into the contralateral optic nerve, and some extended ectopically—dorsal and lateral to the chiasm. Our results indicate that Slit proteins repel retinal axons in vivo and cooperate to establish a corridor through which the axons are channeled, thereby helping define the site in the ventral diencephalon where the optic chiasm forms