Axonal Growth Is Sensitive to the Levels of Katanin, a Protein That Severs Microtubules

Abstract

Katanin is a heterodimeric enzyme that severs microtubules from the centrosome so that they can move into the axon. Katanin is broadly distributed in the neuron, and therefore presumably also severs microtubules elsewhere. Such severing would generate multiple short microtubules from longer microtubules, resulting in more microtubule ends available for assembly and interaction with other structures. In addition, shorter microtubules are thought to move more rapidly and undergo organizational changes more readily than longer microtubules. In dividing cells, the levels of P60-katanin (the subunit with severing properties) increase as the cell transitions from interphase to mitosis. This suggests that katanin is regulated in part by its absolute levels, given that katanin activity is high during mitosis. In the rodent brain, neurons vary significantly in katanin levels, depending on their developmental stage. Levels are high during rapid phases of axonal growth but diminish as axons reach their targets. Similarly, in neuronal cultures, katanin levels are high when axons are allowed to grow avidly but drop when the axons are presented with target cells that cause them to stop growing. Expression of a dominant-negative P60-katanin construct in cultured neurons inhibits microtubule severing and is deleterious to axonal growth. Overexpression of wild-type P60-katanin results in excess microtubule severing and is also deleterious to axonal growth, but this only occurs in some neurons. Other neurons are relatively unaffected by overexpression. Collectively, these observations indicate that axonal growth is sensitive to the levels of P60-katanin, but that other factors contribute to modulating this sensitivity.