How neurons modify the extracellular matrix during nervous system development is poorly understood. Plasminogen-like proteases are required for cell migration and axon outgrowth of the dorsal root ganglia (1, 2) and are implicated in mossy fiber axon branching in the hippocampus (3). The use of proteolytic activity to facilitate axon outgrowth must be carefully controlled and coordinated with instructions from multiple axon guidance molecules. How does a neuron integrate these extracellular cues with protease activity to accurately permit axon growth through time and space?
The
kal-1/anosmin gene is implicated in multiple aspects of neuronal development including cell migration and axon branching in both vertebrates and invertebrates (4-7). In C. elegans, KAL-1 has high affinity for heparan sulfate proteoglycans (HSPGs); key components of the cell surface and extra cellular matrix. In addition, human anosmin exhibits high affinity binding to urokinin-related plasminogen activator (PLAU) in vitro. As such, KAL-1/anosmin is well positioned to integrate HSPG and extracellular matrix cues with the proteolytic activity of plasminogen activators, facilitating accurate axon outgrowth.
PLAU contains a plasminogen protease and kringle domain. Our preliminary data indicates that C. elegans TRY-2 may be orthologous to human PLAU as this is the only C. elegans protease that contains both of these domains. In addition,
try-2(
ok2531) embryos exhibit neuroblast migration defects suggesting a role for plasminogen activity in embryonic development. Genetic analysis is ongoing to establish whether
try-2 functions with other genes required for neuroblast migration, axon outgrowth and KAL-1 dependent axon branching.
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