Abstract
How extracellular molecules influence the direction of axon guidance is poorly understood. The HSN axon of Caenorhabditis elegans is guided towards a ventral source of secreted UNC-6 (netrin). The axon’s outgrowth response to UNC-6 is mediated by the UNC-40 (DCC) receptor. We have proposed that in response to the UNC-6 molecule the direction of UNC-40-mediated axon outgrowth is stochastically determined. The direction of guidance is controlled by asymmetric cues, including the gradient of UNC-6, that regulate the probability that UNC-40-mediated axon outgrowth is directed on average, over time, in a specific direction. Here we provide genetic evidence that a specialized extracellular matrix, which lies ventral to the HSN cell body, regulates the probability that UNC-40-mediated axon outgrowth will be directed ventrally towards the matrix. We show that mutations that disrupt the function of proteins associated with this matrix, UNC-52 (perlecan), UNC-112 (kindlin), VAB-19 (Kank), and UNC-97 (PINCH), decrease the probability of UNC-40-mediated axon outgrowth in the ventral direction, while increasing the probability of outgrowth in the anterior and posterior directions. Other results suggest that INA-1 (α integrin) and MIG-15 (NIK kinase) signaling mediate the response in HSN. Although the AVM axon also migrates through this matrix, the mutations have little effect on the direction of AVM axon outgrowth, indicating that responses to the matrix are cell-specific. Together, these results suggest that an extracellular matrix can regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will be oriented in a specific direction.
Highlights
Axons are guided by cues emanating from the surrounding extracellular environment
These results suggest that an extracellular matrix can regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will be oriented in a specific direction
We show that when the muscle/epidermis extracellular matrix is disrupted by different mutations, UNC-6 still induces the asymmetric localization of UNC-40 in HSN, but the probability of anterior and posterior UNC-40 localization and axon outgrowth increases, whereas the probability of ventrally directed localization and outgrowth decreases
Summary
Axons are guided by cues emanating from the surrounding extracellular environment. A major challenge has been to understand how extracellular cues specify the direction of axon guidance. The neurites soon become restricted to the ventral side of the cell where a ventral leading edge forms This leading edge is just dorsal of a band of longitudinal body-wall muscle cells (Figure 1A, B). At this interface the ventral surface of HSN pauses and expands until, abruptly, neurites extend and invade the specialized basement membrane that separates the muscles and the epidermis. This matrix contains specialized structures that allow the muscle cells to attach to the epidermis. It is somewhat surprising that circumferentially migrating axons transverse this specialized complex matrix instead of taking a seemingly easier route along the matrix at the internal side of the muscle [1]
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